Sjögren Syndrome

Sjögren Syndrome

1 Overview

Summary and Quick Facts

  • Sjögren Syndrome is an autoimmune condition that causes dry eyes and mouth and sometimes other conditions. It may occur alone, or in conjunction with other autoimmune diseases like lupus or rheumatoid arthritis.
  • This protocol will help you understand the causes of Sjögren Syndrome and how it is diagnosed and treated. Learn about cutting-edge research that may lead to new, more effective therapies. Discover several supplements, as well as lifestyle and dietary choices, that may help ease Sjögren symptoms.
  • Awareness of potential triggers of Sjögren symptoms, such as food sensitivities and certain medications, along with eating a healthy, anti-inflammatory diet can help ease troublesome symptoms like dry eyes.
  • Omega-3 fatty acids, such as those found in fish oil supplements, are recommended by the Sjögren Syndrome Foundation as an important part of treatment.

What is Sjögren Syndrome?

Sjögren syndrome is an autoimmune disease that affects the salivary and tear glands, reducing production of tears and saliva. While this syndrome mostly only affects these aspects of health, it can have other systemic manifestations including nerve damage, lung disease, and a significant increase in the risk of developing lymphoma.

Sjögren syndrome may occur alone (primary) or in association with another autoimmune disease (secondary), such as systemic lupus erythematosus (SLE), rheumatoid arthritis, or scleroderma. Patients diagnosed with Sjögren syndrome should be vigilant about screening for related conditions.

Natural interventions such as omega-3 fatty acids and lactoferrin may help reduce inflammation and improve symptoms.

What are the Risk Factors for Sjögren Syndrome?

  • Family history
  • Viral infections such as cytomegalovirus, Epstein-Barr virus, or others
  • Gender – women are nine times more likely than men
  • Age – onset is most common in those aged 55 to 65

What are the Signs and Symptoms of Sjögren Syndrome?

  • Dry eyes and/or dry mouth
  • Dryness in other areas, including the nose, throat, skin, and vagina
  • Additional symptoms may include fatigue, fever, joint pain, among others

What are Conventional Medical Treatments for Sjögren Syndrome?

Note: There is no cure for Sjögren syndrome; treatments generally aim to minimize symptoms and prevent complications.

  • Artificial tears and ophthalmic ointments
  • Cyclosporine eye drops
  • Tear duct plugs
  • Topical steroids
  • Salivary substitutes and stimulants
  • Acetylcholine activators to stimulate saliva production
  • Acetaminophen or non-steroidal anti-inflammatory drugs
  • Corticosteroids
  • Immunosuppressive drugs (eg, cyclophosphamide or hydroxychloroquine)
  • Antirheumatic drugs
  • The monoclonal antibody rituximab

What are Emerging Therapies for Sjögren Syndrome?

  • Autologous serum eye drops made from the patient’s blood may be more effective than traditional artificial tears at treating dry eyes.
  • Lacrimal (tear) gland repair with progenitor cells was effective in animals.
  • Monoclonal antibodies used to treat autoimmune diseases, such as belimumab for SLE, may be effective in Sjögren syndrome as well.
  • Mesenchymal stem cell therapy may suppress autoimmunity and improve symptoms.
  • Topical nerve growth factor may relieve dry eye caused by a variety of conditions.
  • Many Sjögren syndrome patients do not receive a formal diagnosis for many years. The discovery of novel diagnostic biomarkers such as cathepsin S, B-cell-activating factor, and myxovirus resistance protein A can help patients receive earlier diagnoses and prompt treatment.

What Dietary and Lifestyle Changes Can Be Beneficial for Sjögren Syndrome?

  • Eat a well-balanced diet
  • Moisten food with broth or sauce if it is difficult to swallow
  • Drink plenty of liquids
  • Avoid irritants (eg, alcohol and spicy or salty foods)
  • Avoid medications that cause dryness (eg, antihistamines)
  • Quit smoking
  • Get regular dental cleanings and exams every few months
  • Engage in a regular form of exercise
  • Consider acupuncture for relieving dry eyes

What Natural Interventions May Be Beneficial for Sjögren Syndrome?

  • Omega-3 fatty acids. Omega-3 fatty acids reduce inflammation associated with Sjögren syndrome. The Sjögren Syndrome Foundation recommends oral supplementation in their clinical practice guidelines.
  • Gamma linolenic acid. This omega-6 fatty acid has anti-inflammatory properties and was shown to improve dry eye symptoms.
  • White peony extract. Peony glucosides have anti-inflammatory and immune-regulating properties. Peony has been used to treat a range of autoimmune diseases. When supplemented with white peony extract, Sjögren syndrome patients experienced improved salivary gland and tear duct function.
  • Lactoferrin. Low levels of lactoferrin in tears have been associated with increased severity of eye surface damage due to dry eye in patients with Sjögren syndrome. Oral supplementation is an effective treatment option for dry eye conditions.
  • Vitamin D. Vitamin D has been shown to modulate the immune system and suppress autoimmunity. Deficiency is strongly linked to dry eyes.
  • Probiotics. Sjögren syndrome patients with dry mouth have less diverse oral microbiomes and an increased risk of dental problem. Probiotic lozenges may improve oral health.
  • Other natural interventions that may benefit patients with Sjögren syndrome include N-acetylcysteine, maqui berry extract, green tea extract, resveratrol, vitamin B12, and folate.

2 Introduction

Chronic dry eyes and dry mouth can be more than minor annoyances—they may be symptoms of Sjögren syndrome, a systemic autoimmune disease (Patel 2014). Sjögren syndrome affects the salivary and tear glands, reducing saliva and tear production (Nguyen 2009). Women are much more likely to be affected than men (Patel 2014).

Along with dry eyes and mouth, up to 30% of people with Sjögren syndrome also experience a wide range of systemic manifestations including fatigue, joint discomfort, nerve damage, lung disease, and blood vessel inflammation. Importantly, Sjögren syndrome markedly increases risk of lymphoma (a type of blood cancer), so people diagnosed with Sjögren syndrome should be monitored for signs of lymphoma (Mariette 2016; Barone 2016; Rischmueller 2016).

Sjögren syndrome is classified as primary when it occurs alone and secondary when it develops alongside another autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis, or systemic sclerosis (Kurien 2017; Mariette 2016).

Although many factors likely contribute to the development of Sjögren syndrome, studies have found strong links between Sjögren syndrome and cytomegalovirus (CMV)—a common virus to which about half of Americans have been exposed (Kurien 2017; Rischmueller 2016; Mariette 2016; Halenius 2014; Schuster 2014; Bate 2010).

Treatment of Sjögren syndrome ranges from artificial tears and saliva substitutes for symptom relief to immunosuppressive drugs such as methotrexate (Trexall), hydroxychloroquine (Plaquenil), and rituximab (Rituxan). Unfortunately, these more aggressive immunosuppressive treatments are associated with troublesome side effects, and none have been shown to reverse the impaired glandular function characteristic of Sjögren syndrome (Vivino 2016; Mariette 2016; Holdgate 2016; Martinez 2011).

The good news is that scientific research is uncovering promising new treatment approaches for Sjögren syndrome. For instance, chronic B-cell activation is a key feature of the disease, and emerging drugs that deplete B cells, such as belimumab (Benlysta), are undergoing clinical trials (Mavragani 2014; Quartuccio 2016). In a preliminary trial, 60% of participants with primary Sjögren syndrome responded positively to belimumab treatment (De Vita 2015; Ferro 2016; Barone 2016). Using stem cells and nerve growth factor to bring about anti-inflammatory and immune-modulating effects is another approach under investigation. Intravenously administered adult stem cells have been shown to increase the salivary flow rate in Sjögren patients, and topical nerve growth factor has been found to increase tear production in animal models of dry eye (Gromova 2016; Ullah 2015; Lin 2014; Lambiase 2011; Xu 2012).

A variety of interventions using natural products may provide therapeutic benefits in Sjögren syndrome. These integrative treatment options, such as omega-3 fatty acids, lactoferrin, maqui berry extract, and white peony extract, have been shown to improve symptoms and reduce inflammation and autoimmunity. In addition, vitamin D may prevent some complications of Sjögren syndrome (Liu 2014; Zhou 2016; Devendra 2015; Bae 2016; Hitoe 2014; Tincani 2013).

This protocol describes the development, diagnosis, and treatment of Sjögren syndrome, including novel and emerging treatments for the disease, as well as dietary and lifestyle considerations that may reduce symptoms. In addition, several evidence-based natural interventions that have shown promise against Sjögren syndrome in scientific studies are discussed.

3 Causes And Risk Factors

Symptoms of Sjögren syndrome develop when salivary glands and lacrimal (tear-producing) glands are damaged by the immune system (Rischmueller 2016).

Cells that line salivary glands and produce saliva, called epithelial cells, are major targets of the autoimmune attack. Epithelial cells in other organs such as the liver, kidneys, lungs, and thyroid are also frequently damaged by the immune system in Sjögren patients (Rischmueller 2016; Kyriakidis 2014; Mitsias 2006).

Sjögren syndrome is a multifactorial disease caused by interaction among genetic and environmental factors. Several viruses have been implicated in Sjögren syndrome, and multiple potential mechanisms of disease have been proposed (Mariette 2016; Mavragani 2013; Catanzaro 2014; Igoe 2013).

Risk Factors

Genetics and family history. Sjögren syndrome and other autoimmune disorders often cluster in families. Immediate family members of Sjögren patients have up to 12 times the risk of developing Sjögren syndrome compared with the general population (Kuo 2015).

Genetic predisposition to Sjögren syndrome and a number of other autoimmune diseases is associated with variants of the human leukocyte antigen (HLA) gene complex (Rischmueller 2016; Ferro 2016; Tincani 2013; Cruz-Tapias 2012).

Viruses. Viral infections may trigger Sjögren syndrome. Potential viral triggers include (Nakamura 2016; Kurien 2017; Nakamura 2015; Origgi 1988; Igoe 2013):

  • Cytomegalovirus (CMV)
  • Epstein-Barr virus (EBV)
  • Human T-lymphotropic virus type 1 (HTLV-1)
  • Hepatitis C virus (HCV)

EBV reactivation may play a role in Sjögren syndrome initiation and progression. EBV infects over 90% of adults worldwide, but in most people the virus becomes inactive after infection (Petrova 2010; Ho 1988). Increased levels of EBV virus and antibodies have been noted in Sjögren patients, suggesting that ongoing EBV activity may trigger autoimmune processes (Kurien 2017; Draborg 2013).

Gender. Sjögren syndrome is nine times more common in women than men. The gender difference may be related to hormonal factors (Kurien 2017; Rubtsov 2010; Mavragani 2014).

Age. While primary Sjögren syndrome can occur at any age, its onset is most common in those aged 55 to 65 (Rischmueller 2016), and risk remains elevated into older age (Patel 2014).

Associated Conditions

Unlike primary Sjögren syndrome, secondarySjögren occurs in people who have another autoimmune disease (Mariette 2016). A variety of other disorders and conditions have also been associated with Sjögren syndrome (Catanzaro 2014; Bartoloni 2015; Quartuccio 2015; Wong 2014; Martinez 2011; Francois 2016; Kim-Lee 2015; Salliot 2007; Ohtsuka 1992; Selmi 2012; Lindvall 2002; Karp 2010; Jara 2007; Pedro-Botet 1993; Ziavra 2000; Maripuri 2009; Ebert 2012; Nilsson 2015; Baruch 1977; Sarkar 2009; Mialon 1997; Alenghat 2016).

Autoimmune Diseases Associated with Sjögren Syndrome


  • Systemic lupus erythematosus
  • Rheumatoid arthritis
  • Scleroderma
  • Mixed connective tissue disease
  • Pernicious anemia
  • Primary biliary cirrhosis
  • Myositis
  • Autoimmune hepatitis
  • Autoimmune thyroiditis


Other Diseases and Disorders Associated with Sjögren Syndrome


  • Hearing loss
  • Kidney disease
  • Non-Hodgkin’s lymphoma
  • Liver disease
  • Hallucinations
  • Depression
  • Chronic obstructive pulmonary disease (COPD)
  • Bronchitis
  • Anemias
  • Fibromyalgia
  • Vasculitis
  • Atherosclerosis
  • Raynaud’s phenomenon
  • Interstitial pneumonia
  • Pregnancy loss

Cytomegalovirus (CMV) and Sjögren Syndrome

About half of the US population has been exposed to cytomegalovirus (CMV), a member of the herpesvirus family (Bate 2010). CMV may play an important role in the onset and progression of certain autoimmune disorders, including Sjögren syndrome (Halenius 2014; Varani 2011; Schuster 2014).

When healthy adults become infected with CMV, they usually experience no symptoms or mild flu-like symptoms. Once a person has been infected with CMV, the virus remains in the body throughout life (Sansoni 2014; Lancini 2014).

Although chronic CMV may not cause significant symptoms in most people, its lingering presence can contribute to a type of immune system dysfunction known as immune senescence (Sansoni 2014; Savva 2013; Chou 2013). Premature senescence of the immune system, which may be induced by CMV, has been proposed to be a contributing factor in autoimmune disorders (Solana 2012; Prelog 2006; Thewissen 2005).

CMV infects the salivary glands, a primary target of autoimmune attack in Sjögren syndrome. In fact, CMV was originally called “salivary gland virus” (Shillitoe 1982; Smith 1956).

Studies in mice have demonstrated an association between chronic CMV infection and the development of an autoimmune disease with features of Sjögren syndrome. These Sjögren-like features include buildup of immune cells and severe inflammation in the salivary and lacrimal (tear) glands, production of autoantibodies, progressive loss of salivary gland function, and decreased secretion of saliva and tears (Schuster 2014; Ohyama 2006).

An article titled A Common Virus That May Accelerate Immune Senescence, published in the January 2015 issue of Life Extension magazine, discusses the effects of long-term CMV infection in greater detail and explores interventions that may help prevent some of the problems associated with this common virus.

4 Signs And Symptoms

“Sicca syndrome” is the term used to describe the main clinical features of Sjögren syndrome: dry eyes (keratoconjunctivitis sicca) and mouth (xerostomia). Sjögren syndrome can affect other lubricating secretions as well, resulting in dryness in the throat, nose, skin, and vagina (Table 1).

Chronic inflammation and other aspects of Sjögren syndrome can further lead to involvement of organs and tissues throughout the body including joints, lungs, kidneys, liver, stomach, and nervous system (Table 2).

Table 1. Signs and Symptoms of Sjögren Syndrome – Sicca Features

 

Eyes

Mouth

Other

Symptoms

sensation of dry eye

sandy/gritty, itchy, burning sensation

redness; blurred vision; eye fatigue

mucinous discharge, “filmy” sensation

intolerance of contact lenses; need for frequent eye drop use

dry mouth/lips

need to drink fluids often to help swallow food

difficulty chewing/swallowing dry foods

difficulty speaking continuously

sore/burning sensation in mouth

difficulty wearing dentures

decreased saliva production

distortion of taste

dry nose, throat, trachea causing dry cough or hoarseness

symptoms of gastritis or pancreatitis

dry skin

vaginal dryness

painful intercourse

Signs

inflammation of cornea

red eye

absent or cloudy saliva

dry, reddened tongue and oral mucosa

sticky oral mucosa

fissures of the tongue

periodontal disease

increased risk of dental cavities

parotid (salivary) gland inflammation or enlargement, with possible fever, tenderness, redness, or infection

oral candidiasis (yeast infections)

halitosis (bad breath)

skin rashes

photosensitivity

recurrent hives

skin ulcerations

low stomach acid

(Rischmueller 2016; Hajj-ali 2013; Catanzaro 2014; Ichikawa 1981; D'Souza 2014; Pokorny 1991)

Table 2. Extraglandular Manifestations of Sjögren Syndrome

General

  • -Fatigue
  • -Low-grade fever, night sweats, weight loss, fatigue

Lungs

  • -Inflammation and fibrosis of the lungs
  • -Thickening or inflammation of the walls of the bronchial airways

Musculoskeletal

  • -Multiple joint pain
  • -Muscle inflammation
  • -Muscle weakness

Kidneys and Urinary Tract

  • -Inability to produce concentrated urine
  • -Systemic acidosis with high urine pH
  • -Weakness caused by potassium loss
  • -Urinary urgency
  • -Kidney stones

Liver

  • -Enlarged liver
  • -Autoimmune hepatitis

Neurologic

  • -Peripheral neuropathy
  • -Brain white matter lesions
  • -Lesions that resemble multiple sclerosis
  • -Pain or tingling sensation (paresthesia)

Skin and Vascular

  • -Dry skin related to nervous system impairment
  • -Venous blood clots

Gastrointestinal

  • -Acid reflux
  • -Gastritis
  • -Symptoms of irritable bowel syndrome (eg, abdominal pain, diarrhea, constipation, bloating)

(Mariette 2016; Rischmueller 2016; Tobon 2012; Kurien 2017; Kim-Lee 2015; Stalenheim 1997; Vrethem 1990; Colafrancesco 2015; Aasarod 2000; Arman 2017; Kaplan 2002; Chung 2014; Volter 2004; Catanzaro 2014)

Sjögren Syndrome and Risk of Lymphoma

The risk of non-Hodgkin’s lymphoma in people with primary Sjögren syndrome is 10 to 15 times higher than in the general population (Ferro 2016; Nezos 2015). Approximately 5% of primary Sjögren patients develop lymphoma, and most cases are B-cell non-Hodgkin’s lymphoma (Barone 2016).

The reasons for increased lymphoma risk in those with Sjögren syndrome are not precisely known. However, more severe Sjögren syndrome appears to be associated with greater lymphoma risk (Baecklund 2014; Yadlapati 2016).

Most non-Hodgkin’s lymphoma in Sjögren patients develops as mucosa-associated lymphoid tissue (MALT) lymphoma. This type of lymphoma frequently affects organs where Sjögren syndrome is active, especially the salivary glands. Other mucosal surfaces can be affected, including those in the eyes, stomach, and lungs (Rischmueller 2016; Mariette 2016).

Sjögren patients should be carefully evaluated and monitored for lymphoma. Recurrent or persistent swelling of the salivary glands should be brought to the attention of a healthcare provider right away (Andola 2016; Jonsson 2012). Other signs and symptoms include unexplained fever, night sweats, fatigue, unexplained weight loss, itchy skin, and reddened areas on the skin (NIH 2016a; Ferro 2016; Aktan Kosker 2013).

More information is available in the Lymphoma protocol.

5 Diagnosis

Dry mouth and dry eyes (sicca symptoms) are key diagnostic symptoms in Sjögren syndrome, yet are often overlooked as unimportant by both patients and doctors (Brito-Zerón 2016). A study that examined data from 6,110 people with primary Sjögren syndrome found that 98% had at least one of these symptoms at the time of diagnosis and 89% had both (Brito Zeron 2015). Therefore, the presence of dry eyes or dry mouth, and especially both, warrants further investigation into possible Sjögren syndrome (Brito-Zerón 2016).

According to the American College of Rheumatology and the European League Against Rheumatism, the most useful tests in diagnosing primary Sjögren syndrome are (Shiboski 2017):

  • Salivary gland biopsy. Signs of inflammation and white blood cells in salivary gland tissues of the lip mucosa are considered indicative of Sjögren syndrome, but are not always present (Shiboski 2012).
  • Anti-SSA/Ro antibodies. The presence of these antibodies is a key indicator of Sjögren syndrome; however, they can also be seen in patients with other autoimmune diseases (Brito-Zerón 2016).
  • Ocular staining. Eye drops that temporarily stain the surface of the eye allow visualization of changes to the corneal surface associated with excessive dryness and an insufficient tear film (JHM 2017). Dry eyes may be seen in a range of autoimmune and other conditions, including Sjögren syndrome (Generali 2015).
  • Schirmer’s test. This test measures tear secretion in patients with dry eyes using absorbent strips that are inserted under the lower eyelids (Mayo Clinic 2014).
  • Unstimulated whole saliva flow rate. One of the simplest tests involves collection and measurement of saliva produced over several minutes. While the normal rate of salivary flow is 0.3–0.4 mL/minute, a rate of <0.1 mL/minute indicates hyposalivation, possibly, but not necessarily, associated with Sjögren syndrome (Aoun 2016).

The most recent guidelines stipulate that a diagnosis of primary Sjögren syndrome requires both a positive biopsy and a positive anti-SSA test, or one of these along with abnormal results from at least one of the other three tests on this list (Shiboski 2017). Clinical exam and laboratory tests assessing possible systemic manifestations, such as neurological, joint, blood, and skin disorders, can be helpful in identifying early Sjögren syndrome in patients without typical sicca symptoms (Brito-Zerón 2016). In addition, appropriate workup includes investigations for Sjögren complications, such as dental cavities, oral yeast infection, other autoimmune diseases, lymphoma, and thyroid, liver, lung, and kidney diseases (Shiboski 2012; Mayo Clinic 2014).

6 Conventional Treatment

Sjögren syndrome cannot be cured with currently available treatments. Instead, treatments primarily aim to minimize symptoms and prevent complications (Vivino 2016; Kurien 2017).

Dry Eyes

  • Artificial tears and ophthalmic ointments. Topical therapy with artificial tears is an important component of first-line treatment for dry eyes (Saraux 2016). Artificial tears provide lubrication and add volume to the tear. Thicker preparations last longer but may blur vision. Non-irritating preservative-free solutions are preferred, especially when tears are used more than four times per day. Ophthalmic ointments are ideal for bedtime use since they remain on the eye surface longer than artificial tears (Rischmueller 2016).
  • Cyclosporine eye drops. Topical application of eye drops containing cyclosporine, an immunosuppressant, twice daily is safe and effective for most Sjögren patients with eye dryness and inflammation. These eye drops can be used when eye lubricants are not sufficient (Mariette 2016; Ramos-Casals 2012).
  • Tear duct plugs. Ophthalmologists may perform a relatively invasive procedure that involves insertion of plugs into tear duct openings to block drainage. These plugs, known as punctal plugs, provide dry eye relief by preserving natural and artificial tears. Punctal plugs may be temporary (collagen) or permanent (silicon), and are generally well tolerated. Adverse effects include overflow of tears, sensation that something is in the eye, and eye irritation (Rischmueller 2016; Ervin 2010; Chi 2012).
  • Topical steroids. Corticosteroid eye drops, such as 0.1% clobetasone butyrate, can be used as a short-term (≤1 month), medically supervised therapy for moderate-to-severe dry eye symptoms (Aragona 2013).

Dry Mouth

  • Salivary substitutes and stimulants. Important interventions for dry mouth include the use of salivary substitutes (artificial saliva) as a mouthwash to moisten oral tissues. Alternatively, specialized sugar-free chewing gums, fluoride gels, mouthwashes, prescription toothpastes, and lozenges containing agents that stimulate saliva production can be used to relieve dry mouth (Kurien 2017; Rischmueller 2016; Erlichman 1990; Konstantinidis 2007).
  • Pilocarpine and cevimeline. Pilocarpine (Salagen, Pilopine) and cevimeline (Evoxac) are oral drugs indicated only when other therapies do not provide sufficient relief. They work by activating receptors for acetylcholine, a neurotransmitter that stimulates saliva production. Pilocarpine is associated with side effects such as nausea, flushing, sweating, and urinary frequency. Cevimeline activates receptors more selectively, but has similar side effects. Pilocarpine should be used with caution or avoided in patients with heart disease or respiratory disease due to risk of slow heart rate or bronchospasm, and in those taking blood pressure medications due to possible drug interactions (Kurien 2017; Rischmueller 2016; Takakura 2003).

Skin and Vaginal Dryness

  • Lubricants and moisturizers. Lubricants and moisturizers can be used to treat skin and vaginal dryness (Rischmueller 2016).

Systemic Treatments for Severe Sjögren Syndrome

  • Acetaminophen or nonsteroidal anti-inflammatory drugs for musculoskeletal symptoms. Acetaminophen (Tylenol) is a preferred treatment for musculoskeletal symptoms in Sjögren patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used. NSAIDs include ibuprofen, naproxen, and diclofenac (Kurien 2017; NIH 2016a). However, caution should be exercised with frequent or long-term use of acetaminophen or NSAIDs. More information is available in the Acetaminophen and NSAID Toxicity protocol.
  • Corticosteroids. Corticosteroids are sometimes used to treat acute flare-ups of inflammatory arthritis (Kurien 2017; Vivino 2016).
  • Hydroxychloroquine. Hydroxychloroquine is an immunosuppressive drug used to treat inflammatory musculoskeletal pain in primary Sjögren syndrome. Hydroxychloroquine may also be used to treat fatigue in some Sjögren patients. Regular monitoring of the eyes for retinal toxicity is required (Vivino 2016; Mariette 2016; Geamanu Panca 2014; Espandar 2016).
  • Other disease-modifying antirheumatic drugs. If hydroxychloroquine is ineffective for inflammatory musculoskeletal pain, other disease-modifying antirheumatic drugs may be considered. Options include methotrexate, leflunomide (Arava), sulfasalazine (Azulfidine), azathioprine (eg, Imuran), and cyclosporine (eg, Restasis) (Vivino 2016).
  • Cyclophosphamide. Cyclophosphamide is an immunosuppressive drug that has been shown to be effective in the treatment of spinal cord compression disorders associated with autoimmune diseases, including Sjögren syndrome (Valim 2015; Hamming 2015; de Seze 2006). In a study in Sjögren patients with severe neurological symptoms due to spinal cord compression, treatment with monthly infusions of cyclophosphamide together with corticosteroids markedly improved several measures of disability (de Seze 2006; Hamming 2015).

Biologics

  • Rituximab (Rituxan). Rituximab is a monoclonal antibody that may be a useful therapeutic option for cases of persistent swelling of the salivary glands or systemic complications. It works by depleting B cells in the blood. Sjögren patients taking rituximab require close monitoring of possible significant toxic side effects (Vivino 2016; Mariette 2016; Pers 2007).

7 Novel And Emerging Strategies

Autologous Serum Eye Drops

Autologous serum eye drops are made from the patient’s blood, which contains some of the same nutrients normally found in tears. Autologous serum eye drops are a good therapeutic option in severe cases of dry eye that do not respond to other treatments. The components of autologous serum eye drops include vitamin A, anti-inflammatory compounds, and various growth factors that promote healing and increase lubrication of the eye surface. In addition, these eye drops contain immunoglobulins (eg, IgA and IgG) and lysozyme, which have antibacterial properties, and are free of preservatives (Pan 2013; Lin 2014; Foulks 2015; Semeraro 2016).

In a double-blind clinical trial, two weeks of treatment with autologous serum eye drops in patients with severe dry eyes resulted in significantly better symptom improvement than conventional artificial tears (Urzua 2012). Several other clinical studies of autologous serum eye drops in dry eye disease have shown positive effects with long-term (up to one year) treatment (Rybickova 2016; Hussain 2014; Jirsova 2014; Mondy 2015). However, a review of clinical trials found inconsistent results with use of autologous serum eye drops for dry eye. Large, randomized controlled trials are needed to further evaluate their potential benefits (Pan 2017).

Treatment of dry eyes with autologous serum eye drops has a good safety record (Soni 2016; Hussain 2014). Limitations of use of autologous serum eye drops include risk of infection (a rare side effect), inconvenience of preparation, and refrigeration requirements (Foulks 2015; Soni 2016).

Lacrimal Gland Repair

A possible new treatment option for dry eyes involves the use of progenitor cells or stem cells to restore normal function to the eyes’ lacrimal (tear) glands. Like stem cells, progenitor cells can differentiate into specific cell types (Gromova 2016; Ackermann 2015; Tiwari 2014).

In an animal study, progenitor cells isolated from the lacrimal glands of normal mice were injected into the lacrimal glands of mice with a disease similar to Sjögren syndrome. The donor progenitor cells successfully differentiated into lacrimal gland secretory cells and substantially improved glandular structure and function in the diseased mice. Tear production significantly increased in the treated mice compared with saline-injected control mice (Gromova 2017).

Belimumab

Belimumab (Benlysta) is a monoclonal antibody that inhibits B-cell activating factor, a cell-signaling compound that is overproduced in primary Sjögren syndrome and contributes to the autoimmune response. Belimumab, administered by intravenous infusion or subcutaneously, is FDA approved for the treatment of systemic lupus erythematosus (another autoimmune disease) and has undergone early-phase clinical trials in Sjögren syndrome patients (De Vita 2015; Seror 2015; Mariette 2015; Yapa 2016).

In one study, treatment with belimumab for 52 weeks benefited about 60% of patients with primary Sjögren syndrome. Decreases in swelling of salivary glands and systemic disease activity were observed at six months and persisted for more than one year. Belimumab treatment also led to modest improvements in fatigue and pain (De Vita 2015; Mariette 2015).

Belimumab is generally well tolerated. The most common adverse effects include infections, infusion reactions, hypersensitivity, headache, nausea, and fatigue. Insomnia, anxiety, and depression have also been reported (Srivastava 2016; Dubey 2011).

Mesenchymal Stem Cells

Mesenchymal stem cells are found in certain tissues in the body and have the ability to differentiate into a range of different cell types. Mesenchymal stem cells secrete anti-inflammatory molecules and have immune-modulating properties. Stem cells infused into the blood have been shown to migrate to the salivary glands where they suppress inflammation (Ullah 2015; Xu 2012; Mavragani 2013).

In a clinical trial in patients with primary Sjögren syndrome, intravenous mesenchymal stem cell therapy markedly increased salivary flow rate, suppressed autoimmunity, and improved disease symptoms. The treatment was well tolerated with no adverse effects (Xu 2012).

Topical Nerve Growth Factor

Nerve growth factor is a signaling molecule that regulates the growth and maintenance of the nervous system and plays a role in wound healing (Qin 2017). Nerve growth factor has been detected in several tissues outside of the nervous system as well as in human tears. Dry eye appears to increase the concentration of nerve growth factor in tears (Lin 2014; Lambiase 2011; Chang 2008; Chen 2014; Takano 2017). Nerve growth factor eye drops have been shown to increase tear production and density of mucous-secreting cells in a dog model of dry eye (Coassin 2005). Other evidence from animal and human studies indicates that topical application of nerve growth factor may relieve dry eye caused by various conditions (Lambiase 2011; Lambiase 2009; Lee 2005; Chang 2008; Aloe 2015). Larger studies are needed to confirm the efficacy of topical nerve growth factor in treating dry eye.

Innovative Laboratory Testing and Diagnostic Approaches

A challenge for Sjögren syndrome patients is they frequently do not receive a formal diagnosis until many years after their symptoms initially manifest. Earlier diagnosis of Sjögren syndrome may allow for prompt initiation of treatment and improved quality of life (Chen 2015; Hamm-Alvarez 2014).

A number of biomarkers that may be used for early assessment and diagnosis of Sjögren syndrome have been identified. These include cathepsin S, B-cell-activating factor, and myxovirus resistance protein A (Nishikawa 2016; Chen 2015; Hamm-Alvarez 2014).

Cathepsin S. Tear levels of an enzyme called cathepsin S appear able to serve as a cost-effective, fast, and noninvasively measurable biomarker for Sjögren syndrome that may lead to early diagnosis (Hamm-Alvarez 2014).

Markedly elevated levels of cathepsin S have been found in tears of Sjögren patients compared with tears of healthy controls. Tear levels of cathepsin S in Sjögren patients were also higher than levels in people with dry eyes unrelated to Sjögren syndrome and those with other autoimmune diseases (Hamm-Alvarez 2014).

B-cell-activating factor. B-cell-activating factor is involved in the development of several autoimmune diseases. Levels of B-cell-activating factor are increased in blood, tears, and saliva of Sjögren patients. Overproduction of B-cell-activating factor in Sjögren syndrome leads to destruction of glandular cells and decreased production of saliva. Among Sjögren patients, those with lymphoma have higher B-cell-activating factor levels than patients without lymphoma (Nishikawa 2016; Mariette 2016; Maslinska 2015).

Myxovirus resistance protein A. Elevated levels of a cytokine called type I interferon have been found in the blood and salivary glands of Sjögren patients. Type I interferon is a major contributor to chronic inflammation and glandular damage in Sjögren syndrome, and higher levels are associated with more severe disease. Since blood and immune cell levels of myxovirus resistance protein A are significantly correlated with type I interferon activity in individuals with primary Sjögren syndrome, myxovirus resistance protein A has been proposed as a useful disease biomarker (Chen 2015; Nishikawa 2016; Rischmueller 2016; Li 2013).

8 Dietary And Lifestyle Considerations

Dietary Considerations

Dry mouth, a common symptom in Sjögren syndrome, can be a significant burden, causing eating difficulties, increased susceptibility to dental cavities, oral discomfort or irritation, undernutrition, and decreased social interaction. Therefore, ensuring adequate nutrition should be a primary objective for Sjögren patients. The following recommendations may be helpful (Wilkinson 2017; Frosio 2017; Sobhani 1998; Villa 2015; Cassolato 2003; Jensen 2014):

  • Consume a well-balanced diet supplying adequate calories.
  • Moisten foods by adding broths, mayonnaise, yogurt, or sauces to make them easy to swallow.
  • Consume plenty of fluids, especially water, with meals.
  • Eat foods high in fiber to help promote healthy bowel function (eg, fruits and vegetables).
  • Avoid irritants such as alcohol and spicy or salty foods.

Anti-inflammatory diet. Since inflammation is a major feature of Sjögren syndrome, patients are encouraged to consume an anti-inflammatory diet, including omega-3 fatty acid-rich cold-water fish such as salmon, tuna, and mackerel (Foulks 2015; Wilkinson 2017). The typical Western diet is high in pro-inflammatory omega-6 fats and low in anti-inflammatory omega-3 fats. In fact, the ratio of omega-6 to omega-3 fats in Western diets is nearly 17:1, whereas a healthy ratio, according to some researchers, may be closer to 4:1 (Simopoulos 2016; Barabino 2003; Simopoulos 2002).

In the landmark Women’s Health Study, greater dietary intake of omega-3 fatty acids was associated with a lower incidence of dry eye in women aged 45 to 84. In addition, women who had higher omega-6:omega-3 fatty acid intake ratios had increased dry eye risk (Simopoulos 2016; Miljanovic 2005). In a randomized controlled trial of patients with dry eye, 65% of patients who received 1000 mg omega-3 fatty acids from fish daily for three months had improvement in symptoms versus 33% in the placebo group (Bhargava 2013).

Food hypersensitivities. It has been observed that Sjögren syndrome patients who have irritable bowel syndrome-like symptoms may have food hypersensitivities (Kim-Lee 2015). Tests such as the IgG antibody test for specific food sensitivities may help Sjögren patients identify and eliminate problematic foods (Shikhman 2011). One study reported a high prevalence (25%) of gluten sensitivity in Sjögren patients based on inflammatory response to a rectal gluten challenge (Liden 2007). In another clinical study, avoiding food allergens eliminated digestive symptoms such as abdominal pain, bloating, and diarrhea in Sjögren patients (Kim-Lee 2015). In a case study of a patient diagnosed with Sjögren syndrome and gluten sensitivity, following a gluten-free and dairy-free diet in addition to supplemental iron, vitamin D, probiotics, and digestive enzymes, eliminated eye dryness and digestive symptoms such as abdominal pain, bloating, and irregular bowel movements (Shikhman 2011).

Lifestyle Considerations

Eye care tips (Rischmueller 2016; NIH 2016a; Greenbaum 1982; Javadi 2011; Pan 2013):

  • Blink more frequently and avoid extended periods of reading, computer use, and other activities that reduce blinking rate.
  • Avoid medications that can cause dryness such as antihistamines, decongestants, diuretics, and antidepressants.
  • Avoid smoking and smoke exposure.
  • Use caution with cosmetics, facial creams, or eye drops that may irritate the eyes.
  • Protect eyes against dry or windy conditions.
  • Consider using humidifiers at home and in the workplace.

Oral hygiene (Rischmueller 2016; NIH 2016a; Stefanski 2017; Bolstad 2016; Miranda-Rius 2015; Aguirre 1997):

  • Because the rate of early tooth loss in Sjögren patients is about twice as high as in the general population, having regular dental cleanings and a dental exam every 3‒4 months is especially important.
  • Sip or drink water frequently and avoid mouthwashes that contain alcohol.
  • Avoid mouth breathing by treating sinusitis or rhinitis; consider treatment with corticosteroid or saline nasal sprays instead of antihistamines.
  • Floss teeth daily.
  • Avoid sugar between meals.
  • Consult with your physician if you are taking medications that can cause dryness such as antihistamines, decongestants, and diuretics.

Exercise

Aerobic exercise has been shown to significantly improve physical function and reduce fatigue and depression in patients with primary Sjögren syndrome (Strombeck, Theander 2007; Strombeck, Jacobsson 2007). A number of studies have revealed that physical activity is associated with reduced chronic inflammation (Beavers 2010).

Acupuncture

Acupuncture may be a potential treatment option for dry eye management. Some human studies have demonstrated that acupuncture can improve tear secretion and wellbeing in patients with dry eye (Yang 2015). The benefits of acupuncture may be due to modulation of the autonomic nervous system and immune system resulting in decreased inflammation of the eye surface (Lin 2014; Kim, Kang 2012).

In a review of several clinical trials, acupuncture was found to be more effective than artificial tears in various objective measures of dry eye symptoms (Yang 2015). In addition, symptom improvement resulting from acupuncture appears to be longer lasting than that obtained with artificial tears. In a comparison trial, participants with moderate-to-severe dry eye were treated for four weeks with either acupuncture or artificial tears. Similar improvements were seen at the end of treatment; however, only participants who received acupuncture had sustained improvement eight weeks after the end of treatment (Kim, Kang 2012).

9 Integrative Interventions

Omega-3 Fatty Acids

Omega-3 fatty acids help reduce inflammation that contributes to dry eyes in Sjögren syndrome (Liu 2014; Lin 2014; Sargi 2013). In fact, treatment of dry eye with oral omega-3 fatty acids is included in the Sjögren Syndrome Foundation’s clinical practice guidelines (Vivino 2016).

A higher consumption of omega-3 fatty acids relative to omega-6 fatty acids may decrease chronic inflammation and has been associated with a significantly reduced risk of dry eye syndrome (Simopoulos 2016; Liu 2014). In a three-month placebo-controlled study, both fish and krill oil significantly reduced eye redness (an indicator of eye inflammation) in patients with dry eye. Krill oil conferred additional benefits including significantly reduced tear levels of a pro-inflammatory cytokine implicated in autoimmune disease activity. This may have been related to the antioxidant astaxanthin, which naturally occurs in krill oil (Deinema 2017).

Early evidence suggests eye drops containing omega-3 fatty acids may also be an effective option for managing dry eye. In a mouse model of dry eye, treatment with eye drops containing 0.2% omega-3 fatty acids led to improvements in corneal irregularities and decreased levels of inflammatory markers on the eye surfaces (Li 2014). In another animal study, topical treatment with a synthetic precursor of resolvin E1, a compound produced in the body through omega-3 fatty acid metabolism, reduced the inflammatory response, increased tear production, and maintained eye surface integrity in a study in mice with dry eye disease (Li 2010).

Gamma Linolenic Acid

Omega-6 fatty acids from animal fats and corn, soy, and seed oils can have pro-inflammatory effects in the body. However, the omega-6 fatty acid gamma linolenic acid (GLA) has anti-inflammatory properties. GLA is synthesized in the body from the essential omega-6 fatty acid linoleic acid. Substantial amounts of GLA can also be obtained from certain plant-based oils such as black current seed oil, borage oil, and evening primrose oil (Simopoulos 2016; Sheppard 2013; Kawamura 2011; Kapoor 2006; Kim, Yoo 2012).

A controlled trial assessed the effectiveness of supplemental GLA from black current seed oil combined with omega-3 fatty acids from fish oil in postmenopausal women with moderate-to-severe dry eye. Six months of supplementation with GLA and omega-3 fatty acids significantly reduced eye irritation symptoms, maintained smoothness of the eye surface, and decreased eye inflammation and pain (Sheppard 2013).

The benefits of GLA in dry eye may be due to its ability to raise the concentration of an important anti-inflammatory cell-signaling molecule in the tear film (Barabino 2003).

White Peony Extract

Peony glucosides are biologically active constituents from white peony (Paeonia lactiflora) root, a traditional Chinese medicinal herb. Studies indicate peony glucosides have anti-inflammatory, immune-regulating, and pain-relieving properties (Feng 2016; He 2011; Wang 2014). Peony glucosides have been used extensively for the treatment of autoimmune diseases, including Sjögren syndrome (Zhou 2016; He 2011; Feng 2016).

In a randomized, double-blind, placebo-controlled clinical trial, total glucosides of peony (600 mg three times daily for 24 weeks) improved salivary gland function and decreased blood concentrations of inflammatory cell-signaling molecules in primary Sjögren patients (Zhou 2016). A retrospective study compared peony glucosides with hydroxychloroquine sulfate for treatment of Sjögren syndrome. Peony extract increased salivary flow, improved tear production, and decreased levels of an inflammatory marker as effectively as hydroxychloroquine, but was associated with fewer severe adverse effects (Zhang 2007).

Animal studies suggest the anti-inflammatory effects of peony glucosides play a prominent role in its clinical benefits. In a mouse model of Sjögren syndrome, paeoniflorin, an active peony glucoside, was shown to alleviate inflammation in salivary gland epithelial cells (Li, Sun 2016). In another study in a mouse model of Sjögren syndrome, peony glucosides decreased the production of certain inflammatory cytokines (Wu 2016).

Lactoferrin

Lactoferrin is an iron-binding protein found in human milk and other body secretions including saliva and tears. Studies indicate oral supplementation with lactoferrin is an effective treatment option for dry eye diseases such as Sjögren syndrome (Devendra 2015; Pastori 2015; Dogru 2007). Low levels of lactoferrin in tears have been associated with increased severity of eye surface damage due to dry eye in patients with Sjögren syndrome (Danjo 1994).

Among its many functions, lactoferrin has antimicrobial and anti-inflammatory activity, promotes wound healing, and stimulates secretion of nerve growth factor. Lactoferrin can also protect cells and tissues against damage caused by oxidative stress (Vogel 2012; Pastori 2015; Dogru 2007).

In a controlled trial in Sjögren syndrome patients, treatment with oral lactoferrin resulted in significant improvement in tear film stability, eye surface lesions, and dry eye symptoms. These improvements diminished when treatment was discontinued (Dogru 2007). In another controlled trial, lactoferrin was shown to alleviate dry eye symptoms postoperatively in cataract surgery patients (Devendra 2015).

Vitamin D

Vitamin D modulates the immune system and suppresses autoimmunity (Erten 2015; Baldini 2014; Arnson 2007). Vitamin D deficiency has been strongly associated with dry eye and impaired tear function (Demirci 2016; Yildirim 2016). Vitamin D supplementation has been shown to effectively treat dry eye, and may protect against complications of Sjögren syndrome (Bae 2016; Agmon-Levin 2012).

One study found that women, but not men, with Sjögren syndrome had significantly lower vitamin D levels than healthy controls (Erten 2015). In another study, Sjögren-related peripheral neuropathy and lymphoma were more common in those with low vitamin D levels (Agmon-Levin 2012).

In an observational study, patients with dry eye syndrome resistant to conventional treatment were given a single intramuscular injection of 200,000 IU of vitamin D3. Ten weeks after the injection, dry eye symptoms were reduced, tear secretion was enhanced, and inflammation at the eye surface and eyelid margin was decreased (Bae 2016).

N-Acetylcysteine

N-acetylcysteine (NAC) is an amino acid-based compound used in conventional medicine as a mucous-thinning agent. NAC is a precursor to glutathione, an important detoxifying molecule in the body that protects cells against oxidative injury (Rushworth 2014).

In Sjögren syndrome, NAC has been used to stimulate saliva flow and tear secretion in the management of dry eyes and mouth (Ramos-Casals 2012). In a double-blind crossover trial, treatment of Sjögren patients with 200 mg NAC three times daily resulted in considerable improvement in mouth and eye dryness. Damage to the eye surface was also improved (Walters 1986).

Maqui Berry Extract (Aristotelia chilensis)

Maqui berry (Aristotelia chilensis) is a tropical berry rich in anthocyanin pigments, which give the berries a dark red or purple color (Watson 2015). In its native Chile, maqui berry has been used for centuries as a traditional medicine to promote wound healing and improve stamina and strength (Romanucci 2016).

In a trial of 13 subjects diagnosed with moderately dry eyes, treatment with either 30 mg or 60 mg maqui berry extract resulted in substantial improvement in tear fluid volume within 30 days. After 60 days of treatment, improvement was sustained in those receiving 60 mg per day, with a nearly 48% increase in tear production compared with baseline, but had diminished slightly in those receiving 30 mg per day. A substantial improvement in dry eye-related quality of life score—a patient-reported measure of eye function, comfort, and symptoms—was also reported in the 60 mg group (Hitoe 2014).

Probiotics

Changes in composition and diversity of the human microbiomeautoimmune diseases (Belkaid 2014; McLean 2015; Karczewski 2014). Ingestion of probiotics improves microbiome health and may modulate autoimmunity (Chae 2012; Hemarajata 2013; de Sousa Moraes 2014; de Oliveira 2017).

Bacteria not only colonize the lining of the intestine, but other mucosal surfaces as well, including those of the mouth and eye (Karczewski 2014; Li, Zou 2016; Terzulli 2015). One study found that the oral microbiome in Sjögren patients differed from that of healthy controls, and was less diverse (Li, Zou 2016).

Sjögren patients with dry mouth have an increased risk for dental caries, periodontal disease, halitosis (bad breath), and oral candidiasis (thrush) (Rischmueller 2016). In a double-blind placebo-controlled trial, administration of lozenges containing the probiotic Streptococcus salivarius strain BLIS M18 over a three-month period significantly reduced formation of dental plaque in children with dental caries. A subgroup of children who demonstrated the most effective bacterial colonization also exhibited reduced counts of Streptococcus mutans, a bacterium that contributes to tooth decay (Burton 2013).

Probiotic lozenges containing Streptococcus salivarius strain BLIS M18 have also been shown in a study in adults to be effective in reducing moderate-to-severe gingivitis and moderate periodontitis (Scariya 2015). A review of studies concluded that oral probiotics are a promising emerging intervention for the treatment and prevention of oral diseases (Saha 2012).

Green Tea Extract

Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol component of green tea (Camellia sinensis) leaves. Animal preclinical studies indicate EGCG has preventive and therapeutic potential in Sjögren syndrome (Dickinson, DeRossi 2014; Dickinson, Yu 2014; Cavet 2011; Ohno 2012; Gillespie 2008). In an animal study, EGCG effectively protected mouse salivary glands from autoimmune-induced inflammation (Gillespie 2008).

Levels of three important enzymes that counteract cell damage caused by free radicals are decreased in affected glandular tissues in Sjögren patients. Findings from preclinical studies suggest EGCG may help restore these enzyme levels (Dickinson, DeRossi 2014).

Resveratrol

Resveratrol is a plant polyphenol with anti-inflammatory, oxidative stress-reducing, and immune-modulating effects. Results from animal studies show resveratrol can have beneficial effects in immune-mediated conditions, including Sjögren syndrome (Inoue 2016; Svajger 2012).

In a study on mice with impaired salivary gland function, resveratrol significantly increased secretion of saliva compared with the control group. Enhanced production of an anti-inflammatory cytokine in the salivary glands of the resveratrol-treated mice appeared to have contributed to the beneficial results (Inoue 2016).

Iron, Vitamin B12, and Folic Acid

Iron and vitamin deficiencies frequently occur in individuals with primary Sjögren syndrome. In a study in Sjögren patients, over half of participants had an iron deficiency, and a significant portion of participants had vitamin B deficiencies. These nutrient deficiencies can affect the function of the salivary and lacrimal (tear) glands, as well as the immune system (Lundstrom 2001).

Vitamin B12 deficiency in Sjögren syndrome results primarily from malabsorption of this vitamin. This inability to absorb B12 (as well as iron and folate) is related to low stomach acid and/or gastritis, common manifestations of Sjögren syndrome (Andres 2001; Kim-Lee 2015; Kines 2016; Sugaya 1995; Maury 1985).

Low blood levels of vitamin B12 and folate are associated with elevated plasma levels of homocysteine. High homocysteine levels promote neurodegeneration and increase risk of cardiovascular disease (Stanger 2009; Ganguly 2015). Early detection of these nutrient deficiencies and repletion with appropriate oral supplementation may prevent potential serious complications and protect the overall health of people with Sjögren syndrome (Andres 2001).

Vitamin B12 and Folate Deficiencies in Sjögren Syndrome: Cardiovascular and Cognitive Risks

Deficiencies of vitamin B12 and folate are common in people with Sjögren syndrome (Lundstrom 2001). A deficiency of these B vitamins can lead to elevated blood levels of homocysteine—a molecule that is toxic to the inner arterial lining and significantly increases cardiovascular disease risk. Increased homocysteine levels also trigger damage to the nervous system, and have been linked to cognitive impairment, dementia, depression, and Alzheimer and Parkinson disease (Ganguly 2015; Mao 2016; Wright 2008).

High plasma concentrations of homocysteine have been associated with various diseases of the eye, including dry eye (Wright 2008; Sekeryapan 2013). In one study, elevated plasma homocysteine was detected in nearly 44% of dry eye patients compared with approximately 33% of controls (Sekeryapan 2013). In a study in patients with primary open-angle glaucoma, participants who also had dry eye disease had significantly higher homocysteine levels in tears and blood than those without dry eye disease (Roedl 2008).

Vitamin B12 and folate have been shown to reduce homocysteine levels (Ganguly 2015; Wright 2008). In an analysis of a major stroke prevention trial, the risk of stroke, heart attack, and death decreased by 24% in stroke survivors older than 67 years who were given high-dose vitamin B12 injections to lower homocysteine levels (Towfighi 2014). This finding of greater benefit from homocysteine-lowering therapy in older individuals in consistent with the fact that damage to the arterial lining may sometimes take decades to eventually manifest as overt vascular disease (NIH 2016b; Funk 2012; Vita 2005). People with Sjögren syndrome should strive to maintain good vascular health, as vascular inflammation due to primary Sjögren syndrome may be a risk factor for ischemic stroke (Yang 2016).

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