What does Sjögren's disease mean and is it dangerous?

• Types of disease
• Reasons for development
• Pathogenesis
• Manifestations
• Diagnostic methods
• Treatment Options
• Innovative treatment in Belgium
• Complications and prognosis
• Clinics for the treatment of Sjögren's syndrome in Belgium

Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disease of unknown origin that affects the exocrine glands, especially the lacrimal and salivary glands.
Symptoms of dry mucous membranes and conjunctiva (sicca symptoms) are the most characteristic signs of this disease. But it can also manifest itself as multiple pathological changes in different organs and systems. Sjögren's syndrome is named after the Swedish ophthalmologist Henrik Sjögren (1899–1986). In 1929, he described a patient who complained of dry eyes, dry mouth, and joint pain. He noted that the combination of these symptoms could potentially be a separate disease, which he defined as "keratoconjunctivitis sicca." The disease was subsequently named after him.

The disease most often affects women, and the average age of onset is 50-60 years.

Because of the wide variety of signs and symptoms, patients with Sjögren's syndrome often see doctors from a variety of specialties, such as ophthalmologists, ENT doctors, or dentists. As a result, up to half of cases remain undiagnosed.

Forms of the disease and features of its course

There are two types of disease - primary and secondary.

Primary Sjögren's syndrome (pSS) occurs in the absence of other autoimmune diseases and is characterized primarily by keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth), collectively called sicca syndrome. Most patients with pSS have two specific antibodies to the antigens Ro (SS-A) and La (SSB).

Secondary Sjogren's syndrome (SSS) occurs as part of other autoimmune diseases.

It may accompany:

• systemic lupus erythematosus 15–36%;
• rheumatoid arthritis - 20–32%;
• limited or progressive systemic sclerosis - 11–24%;
• multiple sclerosis, autoimmune hepatitis or thyroiditis - rare;

The term “secondary” does not describe the chronological sequence of manifestations. That is, the underlying disease can manifest itself for a long time only as Sjögren's syndrome with sicca symptoms and only later manifest itself in the form of its typical symptoms.

Symptoms of Sjögren's disease

The appearance of eye symptoms in Sjögren's disease is caused by decreased secretion of tears (tear fluid). In this case, patients feel a burning sensation, “scratching” and “sand” in the eyes. Subjective symptoms are accompanied by itching and redness of the eyelids, accumulation of viscous secretions in the corners of the eyes, narrowing of the palpebral fissures, and decreased visual acuity. Dry keratoconjunctivitis develops - inflammation of the cornea along with the conjunctiva of the eye.

The salivary glands increase in size in Sjögren's disease. In a third of patients, as a result of enlargement of the paired parotid glands, a characteristic change in the oval of the face is noted, which in the literature is called “hamster face”. Typical symptoms of Sjogren's disease also include dry lips and oral mucosa, stomatitis, seizures, multiple dental caries (usually cervical localization). If in the early stage of Sjogren's disease dry mucous membranes are noted only during physical activity and excitement, then in the severe period the feeling of dryness is constantly observed, forcing the patient to frequently moisten the mouth and wash down food.

Upon examination, a bright pink color of the mucous membranes, their slight injury upon contact, dry tongue, and a small amount of free saliva of a foamy or viscous nature are revealed. Against this background, the addition of a secondary (viral, fungal, bacterial) infection leads to the development of stomatitis. The late stage of Sjogren's disease is characterized by severe dryness of the oral cavity, leading to swallowing and speech disorders, cracked lips, keratinization of areas of the oral mucosa, folded tongue, and lack of free saliva in the oral cavity.

There is hypofunction of other exocrine glands with symptoms of dry skin, nasopharynx, vulva and vagina, the development of tracheitis, bronchitis, esophagitis, atrophic gastritis, etc. With Sjögren's disease, articular syndrome such as polyarthralgia or polyarthritis, impaired sensitivity of the feet and hands, and neuropathy may be observed trigeminal nerve and facial nerve, hemorrhagic rashes on the limbs and torso, fever, myositis, hepato- and splenomegaly.

Causes of Sjögren's syndrome

The cause of Sjögren's syndrome is not yet entirely understood. The presence of activated salivary gland epithelial cells expressing major histocompatibility complex (MHC) class II molecules and the identification of inherited markers of susceptibility suggest that environmental or endogenous antigens trigger the inflammatory response in susceptible individuals.

Association with human leukocyte antigen

The frequency of the presence of the HLA-DR52 autoantigen in patients with primary SS is estimated at 87%, but it is also significantly increased in secondary Sjögren's syndrome.

Genetic associations for Sjögren's syndrome vary among ethnic groups. For example, in Europeans this condition is associated with human leukocyte antigens (HLA)-DR3, HLA-DQ2, HLA-B8, while in Hispanics it is associated with HLA-DR5.

Some evidence suggests that the true association of Sjögren's syndrome may be with HLA-DQA1, which is in linkage disequilibrium with HLA-DR3 and HLA-DR5.

Possible triggers of the disease

Viruses are considered good candidates for environmental triggers, although no proof of causation has yet been provided.

Damage or death of cells due to viral infection or other causes can trigger antigens to Toll-like receptors on dendritic or epithelial cells, which, when activated, begin to produce cytokines and chemokines.

Sex hormones

Sex hormones may influence the immunological manifestations of primary Sjögren's syndrome because the disease occurs much more often in women than in men. The prevalence of serological markers is generally lower in male patients than in female patients. Although the role of sex hormones (eg, estrogens, androgens) in the pathogenesis of primary SS remains unknown, deficiency of adrenal and gonadal steroid hormones likely affects immune function.

Forecast

Sjögren's syndrome can damage vital organs with a transition to a stable state, gradual progression, or, conversely, long-term remission. This behavior is also common in other autoimmune diseases.[9]

Some patients may have mild symptoms of dry eyes and mouth, while others develop serious complications. Some patients are completely helped by symptomatic treatment, others have to constantly struggle with deterioration of vision, constant discomfort in the eyes, often recurrent infections of the oral cavity, swelling of the parotid salivary gland, difficulty chewing and swallowing. Constant loss of strength and joint pain seriously reduce the quality of life.

In some patients, the pathological process involves the kidneys - glomerulonephritis, leading to proteinuria, impaired renal concentrating ability and distal renal tubular acidosis.

People with Sjögren's syndrome have a higher risk of developing non-Hodgkin's lymphoma compared to healthy people and people with other autoimmune diseases.[10] About 5% of patients develop some form of lymphoma.[11]

In addition, it has been found that children of women with Sjögren's syndrome during pregnancy have a higher risk of developing neonatal lupus erythematosus with congenital heart block.[12]

Pathogenesis

In people with a genetic predisposition, when exposed to an external or hormonal trigger, the regulation of immune activity in the epithelial cells of the glands is disrupted. As a result, chemokines and adhesion molecules (immune patterns) are released. This causes dendritic cells and lymphocytes (T cells and B cells) to migrate into the glands. Dendritic cells in the glands produce high levels of interferons (IFN), which causes further retention of lymphocytes in the tissues and their subsequent activation.

Interferons stimulate the production of B cell activating factor (BAFF) by epithelial cells, dendritic cells, and T cells.

BAFF promotes irregular maturation of B cells, resulting in the formation of autoimmune B cells that locally secrete autoantibodies that ultimately damage glandular cells.

When diagnosed with Sjögren's syndrome, the pathogenesis of nonglandular manifestations manifests itself in part as hypergammaglobulinemia and the production of multiple autoantibodies, especially ANA and RF. This is likely due to the activation of polyclonal B cells, but the exact cause of this enhanced activation is unknown.

Involvement of other organs and tissues may result from exposure to these antibodies, immune complexes, or lymphocytic infiltration and occurs in one third of patients with SS. Long-term hyperstimulation of B cells can lead to defects in their differentiation and maturation, which may explain the significantly increased incidence of lymphoma in these patients.

Symptoms

With a disease such as Sjögren's syndrome, the symptoms are very varied. Most patients are women, but it can also affect men and children. The beginning is insidious. The first signs of Sjögren's syndrome can be easily missed or misinterpreted, and as a result, a correct diagnosis may take several years to be made.

Symptoms of sicca (dry eyes and dry mouth)

Although dry eyes and dry mouth will be the most common symptoms in patients with Sjögren's syndrome, most patients reporting these symptoms have other underlying causes. The frequency of sicca symptoms increases with age. At the same time, more than a third of older people have sicca symptoms in one form or another. Whether this becomes part of the normal aging process (associated with fibrosis and atrophy observed in some lip biopsy studies) or is due to the accumulation of comorbidities is unclear.

Patients may describe the effects of dry mouth in different ways.

• Inability to eat dry foods (such as crackers) because they stick to the roof of the mouth.
• Tongue sticks to the roof of your mouth
• Difficulty speaking for long periods of time or developing hoarseness.
• Altered sense of taste.

Dry eyes can be described as red, itchy and painful. However, the most common complaint is a feeling of sand in the eyes. Symptoms usually worsen during the day, possibly due to evaporation of the already meager water layer.

Mumps

Mumps (inflammation of the parotid gland), often bilateral, is a common manifestation of Sjögren's syndrome. It usually has a recurrent course and rarely causes visible manifestations in the form of glandular tumors. Most often it is discovered by a doctor during an examination.

Skin symptoms

Nonvasculitic skin manifestations of Sjögren's syndrome include:

• dryness;
• dermatitis;
• itching;
• erythema.

Cutaneous vasculitis develops only in some patients with SS, especially those with hypergammaglobulinemia or cryoglobulinemia. Raynaud's phenomenon occurs in approximately 20% of patients.

Pulmonary symptoms

Patients with Sjögren's syndrome may develop dryness of the tracheobronchial mucosa (xerotrachea), which manifests itself as a dry cough. Less commonly, patients develop shortness of breath due to interstitial lung disease, which is usually mild.

Gastrointestinal symptoms

A dry throat or esophagus often leads to difficulty swallowing. In this case, patients usually talk about food getting stuck in the throat. Insufficient saliva can lead to impaired acid clearance, gastroesophageal reflux and esophagitis.

Rarely, patients develop acute or chronic pancreatitis or malabsorption due to pancreatic insufficiency. Patients with Sjögren's syndrome are at increased risk of delayed gastric emptying, which can cause early satiety, upper abdominal discomfort, nausea, and vomiting.

Heart symptoms

Pericarditis or pulmonary hypertension with accompanying symptoms are also characteristic of Sjögren's syndrome. Orthostatic symptoms, associated with impaired autonomic control of blood pressure and heart rate, are associated with increased severity of SS.

Neurological symptoms

According to various studies, the occurrence of central nervous system (CNS) damage in Sjögren's syndrome is 8-40%, with manifestations such as myelopathy, optic neuropathy, seizures, cognitive dysfunction, and encephalopathy. Attempts should be made to distinguish between other causes of these symptoms, including concomitant SLE, multiple sclerosis, cerebrovascular disease, or Alzheimer's disease.

Sensory, motor, or sensorimotor peripheral neuropathy, often subclinical, can be found in up to 55% of unselected patients with SS.

Kidney symptoms

Interstitial nephritis is the most common form of kidney damage in Sjögren's syndrome.

Interstitial cystitis with symptoms of dysuria, frequency, urgency, and nocturia is also common in SS.

Additional symptoms

Patients with Sjögren's syndrome may report fatigue, joint pain, and sometimes joint swelling. Careful analysis of the systems is necessary to distinguish them from manifestations of other disorders. Fibromyalgia is common in patients with SS, with an incidence of approximately 31%.

Women also experience vaginal dryness, which can lead to dyspareunia, vaginitis and itching.

Secondary Sjögren's syndrome

It is usually milder and sicca symptoms become dominant. Unlike patients with primary SS, those with the secondary type have significantly fewer systemic manifestations.

In secondary Sjögren's syndrome, the symptoms of the primary disease predominate. Secondary SS does not affect the prognosis or outcome of the underlying disease.

4.Treatment

There is currently no etiopathogenetic treatment. Palliative therapy is prescribed - salivary stimulants, artificial tears, as well as, as necessary, non-steroidal and hormonal anti-inflammatory drugs, antibiotics and other drugs for symptomatic treatment.

With timely initiation of treatment, the prognosis is favorable; if it is delayed, it is questionable, since the autoimmune process that progresses over a long time leads to the development of severe complications from a number of key body systems. In such cases, disability often occurs, and certain life-threatening conditions may develop.

Diagnosis of Sjögren's syndrome

Schirmer test

If Sjögren's syndrome is suspected, diagnosis using filter paper is often the first test. A filter paper test strip is placed near the lower conjunctival sac to measure tear production. Healthy people wet 15 mm or more of paper after 5 minutes. A positive test occurs when less than 5 mm of the strip is wet after 5 minutes.

Rheumatoid factor

RF is present in 52% of patients with primary Sjögren's syndrome and in 98% of patients with secondary disease occurring even in the absence of rheumatoid arthritis. The presence of RF was independently associated with an increased risk of lymphoma in patients with primary Sjögren's syndrome.

Antinuclear antibodies

Autoimmune ANA antibodies are usually present in all patients with Sjögren's syndrome.

Coloring

Rose Bengal is an aniline dye that stains epithelial surfaces with changes characteristic of this disease. Staining of the conjunctiva can be detected with the naked eye. Slit lamp examination is performed after rose bengal staining to detect abnormal uptake in the cornea.

Lissamine green staining works similarly but causes less eye irritation. Fluorescein staining can be used to identify corneal lesions.

Saliva testing

Sialometry is a good measure of the degree of reduction in salivary blood flow and helps identify xerostomia, but the results are not specific.

Diagnostics

Diagnosis of Sjögren's syndrome is complicated by the variety of symptoms, as well as their similarity to symptoms of other diseases. However, a combination of certain tests can help make a diagnosis:

1. ANA profile (anti-nuclear antibody). Typical markers are SSA/Ro and SSB/La, of which SSB/La is more specific; SSA/Ro is often associated with other autoimmune conditions, but is often present in patients with Sjögren's syndrome.[6][7]
2. Schirmer's test. Evaluates tear production: a strip of filter paper is placed behind the lower eyelid for five minutes, then the length of the paper moistened with tears is measured. Less than 5 mm speaks in favor of Sjögren's syndrome. It must be remembered that the function of tear secretion decreases with age, as well as with some other disorders.
3. Sialometry. Normally, when stimulated with ascorbic acid, approximately 2.5-6.0 ml of saliva is released in 5 minutes.
4. Unstimulated saliva collection. The patient collects saliva into a test tube for 15 minutes. A result of less than 1.5 ml is considered positive.

Treatment

The main approach to interdisciplinary care for patients with Sjögren's disease is:

• measures to improve quality of life;
• pharmacological as well as non-pharmacological treatment to control disease activity;
• managing the risk of developing lymphoma.

With a diagnosis such as Sjögren's syndrome, treatment must take into account the heterogeneity of the disease.

But most often, treatment comes down to combating the symptoms of dryness.

Moisturizing eye drops of the “artificial tear” class are used. Or, in a more advanced version, gels and gel films that prevent dryness. It is recommended to apply moisturizing creams and lotions to the outer skin.

If artificial tears do not help, medications are prescribed to enhance tear production:

• Cequa;
• Lacrisert;
• Restasis.

Lacrisert is a flat, tiny capsule. It is placed into the eye with a special applicator, usually once or twice a day. Cequa and Restasis come in the form of drops that are used twice daily.

To treat dry mouth, your doctor may prescribe medications that increase the amount of saliva, including:

• Cevimeline (Evoxac);
• supersaturated calcium phosphate (NeutraSal);
• Pilocarpine.

It is recommended to apply moisturizing creams and lotions to the outer skin.

For the treatment of arthralgia, NSAIDs are used - nimesulide, lernoxicam, ethacridic acid.

Prevention

To date, there is no specific prevention for Sjögren's syndrome. The only thing is that you can prevent frequent exacerbations of the disease and slow down its progression in the following ways:

1. Constant use of medications prescribed by the attending physician.
2. Carrying out measures to prevent the development of secondary infections.
3. Limiting exposure to external factors that increase symptoms.
4. Elimination of stressful situations.
5. Stay away from sources of harmful radiation to the body.
6. Daily sufficient air humidification in the living room.

Sjögren's syndrome is characterized by frequent alternation between periods of remission and exacerbation. Regular loss of strength, muscle weakness, joint pain - all this reduces the quality of life of a person suffering from this chronic disease. High mortality is observed in cases where the disease is accompanied by acute pneumonia, renal failure, or oncological pathology. Sjogren's syndrome is treated by specialists quite successfully, if the first warning symptoms are not overlooked.

Treatment of Sjögren's syndrome in Belgium

B-cell depletion is a promising form of therapy that is being used in clinics in Belgium to treat patients with Sjögren's syndrome. The effect is achieved using anti-CD20 or anti-CD22 therapy.

Rituximab (anti-CD20) is a monoclonal antibody that targets the CD20 antigen found on B cells. The drug's mechanism of action includes complement-dependent cytotoxicity, growth inhibition, and B cell apoptosis. Reducing the number of B cells reduces the amount of autoantibodies produced and therefore the effects of the disease. It has been shown to be effective in reducing sicca symptoms and normalizing salivary gland function.

A prospective study of 78 patients with primary SS treated with rituximab also reported significant improvement in extraglandular manifestations as measured by EULAR (European League Against Rheumatism). Several small studies of rituximab have found improvement in arthralgia, regression of parotid swelling, and improvement in immune thrombocytopenia.

Leflunomide/Hydroxychloroquine combination therapy resulted in significant reductions in pathological scores and was not associated with serious side effects in a small phase 2a randomized clinical trial in the Netherlands. This served as the basis for the approval of a comprehensive treatment regimen in clinics in Belgium.

Also, extensive trials of other most promising treatment methods are being carried out in medical centers in Belgium, such as:

• anti-CD22 agents;
• anti-BAFF agents;
• anti-IL-1 agents;
• interferon type 1
• anti-T cell agents

Symptoms

If a patient is diagnosed with Sjögren's disease, the symptoms of the pathology will vary depending on the stage and form.
It is also necessary to take into account that in addition to the glands themselves, damage can also affect internal organs (more often this occurs during exacerbation of the disease). This usually affects:

• thyroid;
• kidneys;
• liver;
• epidermis;
• organs of the respiratory system;
• articulations.

If the disease affects internal organs, treatment should not be delayed. If you ignore the initial symptoms, the likelihood of developing dangerous complications increases. That is why, when the first signs of the disease appear, you need to make an appointment at the clinic as soon as possible for diagnosis and treatment.

In most cases, when visiting doctors, patients complain of the following symptoms:

1. Feeling of dryness and feeling of sand in the eyes. If dry conjunctivitis is accompanied by an infection, the disease may be accompanied by more serious symptoms - ulcers and perforation of the cornea.
2. Feeling of dryness in the mouth. In the chronic form of the disease, there is a possibility of developing cervical caries. The patient may also experience difficulty swallowing food.
3. Excessive dryness and discomfort in the vagina (this symptom will be most pronounced after sexual intercourse).
4. Dry crusts on the mucous membranes of the nose, dryness of the pharynx and larynx.
5. Peeling of the epidermis.
6. If the disease affects the gastric tract, the patient may develop gastritis, accompanied by secretory insufficiency. Also, patients often encounter damage to the duodenum. Such a deviation can be suspected even during palpation, since when palpating the abdominal cavity a person will experience pain.
7. Painful sensations in the joints. With Sjögren's syndrome, destructive changes in the joints often develop.
8. Increased size of the parotid glands (this symptom may also be accompanied by pain).
9. Excessive dryness of the respiratory tract, leading to a constant cough and burning sensation in the throat.
10. An increase in the size of the lymph nodes, as well as a change in the size of the liver and kidneys.
11. Muscle pain.

Photos and videos of manifestations of this disease can be seen on numerous websites on the Internet.

In many women, against the background of this disease, susceptibility to drugs increases, especially often to non-steroidal anti-inflammatory drugs and some antibiotics. This deviation causes difficulties in prescribing an appropriate treatment regimen.

Complications and prognosis

Complications associated with Sjögren's syndrome.

• The emergence of disorders associated with SS such as systemic lupus erythematosus and rheumatoid arthritis.
• Parotid gland infection, usually staphylococcal, streptococcal, or pneumococcal, involves unilateral worsening of symptoms as well as tenderness, warmth, and erythema.
• Appearance of parotid gland tumors - Watch for unusually firm or unilateral enlargement of the parotid gland.
• Pregnant patients with anti-Ro/SS-A antibodies are at risk of fetal loss, complete heart block in the fetus, and lupus in the newborn.
• The appearance of pseudolymphomas (pleomorphic cells that do not meet the criteria for malignancy) and non-Hodgkin B-cell lymphomas.

Sjogren's syndrome generally has a good prognosis. In patients who develop a comorbid disorder (SLE, lymphoma), prognosis is more closely related to it. Interestingly, primary Sjögren's syndrome is associated with reduced risk factors for cardiovascular events such as myocardial infarction and stroke compared with SLE.

Patients with primary disease who do not develop a lymphoproliferative disorder have a normal life expectancy.