Sjögren's syndrome – Treatment in Israel

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.

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.

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.

Forms and stages of the disease

The following forms of Sjögren's syndrome are distinguished:

1. Chronic
. This form is characterized by a slow flow. The patient has no obvious symptoms; the exocrine glands are mainly affected and their function is impaired.
2. Subacute
. Sjögren's syndrome occurs unexpectedly and is accompanied by symptoms of inflammation, fever, and affects not only the glands, but also internal organs. According to the severity of symptoms, early, severe and late stages of Sjögren's syndrome are distinguished. The following degrees of pathology activity are distinguished:
3. With a high
degree of activity of Sjogren's syndrome, a person develops signs of inflammation of conjunctivitis, cornea and gums, mumps, enlarged lymph nodes, liver and spleen.
4. With a moderate
course of the pathology, partial destruction of the glandular tissue is observed.
5. With minimal
activity of Sjogren's syndrome, the salivary glands are involved in the pathological process, which causes disruption of their function and the appearance of xerostomia. Gastritis and keratoconjunctivitis may also develop.

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.

Symptoms of Sjögren's disease

This disease has a number of clinical manifestations. This is due to the fact that the process itself is autoimmune, and components of the immune system are found throughout the body. An autoimmune process is damage to the body's tissues by the body's own immune system. In this article, attention is paid to eye damage, and accordingly, the symptoms are considered from the eyes.

Patients present the following complaints:

itching in the eye area;
sensation of a foreign body in the eye;
photophobia.

Changes in the eyes give a picture of dry keratoconjunctivitis. The hypofunction of the lacrimal gland is due to the fact that its tissue is abundantly infiltrated with lymphocytes.

Additionally, disorders of the gastrointestinal tract and respiratory tract are noted (the glands there are also infiltrated with lymphocytes). Joints are quite often affected.

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.

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.

Meige's disease

At the end of the last century, Meige described the syndrome of limited chronic edema, which is characterized by a tendency towards stability and a chronic course.

Etiology

Meige's disease, like Quincke's edema, develops in individuals with constitutional inferiority of the hypothalamic region. The effect of exogenous or endogenous factors matters. Provoking factors can be infectious diseases, traumatic factors, and hypothermia.

Features of clinical manifestations

Meige's edema is most often localized on the face and mucous membranes in both men and women aged 20-40 years. Sometimes being symmetrical, the swelling is dense and does not leave a hole after pressing on it with a finger.

The duration and frequency of such crises vary. Sometimes they occur once a week or a month, or even less frequently. Swelling lasts from 2-5 hours to 10 days or longer. However, the swelling does not disappear completely; a somewhat dense area of skin and subcutaneous tissue remains. In some cases, tissue compaction increases very slowly, the process drags on for years; in other cases, the process develops very quickly, the affected part of the body loses its normal shape.

The appearance of edema is accompanied by a more or less pronounced general reaction in the form of malaise, fever, chills, and in some cases severe headaches, confusion, and dyspeptic disorders.

Insufficient knowledge of the characteristics of the clinical manifestations of Meige's disease leads to the fact that swelling developing on the face and oral mucosa is associated with the pathology of the dental system and treatment is prescribed that does not give a positive effect.

Treatment

Antihistamines are prescribed (diphenhydramine, suprastin, diprazine tablets, calcium chloride 10%, one tablespoon 3-4 times a day after meals), ephedrine hydrochloride 0.05 g 3 times a day for 2 weeks, atropine-like drugs (sulfate atropine 0.25-0.5 twice a day, belloid 1-2 tablets 3 times a day; courses of anti-inflammatory treatment: antibiotics, gamma globulin, etc.

A course of treatment with glucocorticoids (prednisolone, dexamethasone, etc.) is recommended.

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

Rossolimo-Melkerson-Rosenthal syndrome

Described by G.I.Rossolimo in 1905, Melkerson in 1928 and Rosenthal in 1931.

Etiology

In the mechanism of development of this syndrome, constitutionally determined insufficiency of the hypothalamic region is important. Damage to the hypothalamic region can be the result of exposure to various exogenous and endogenous factors.

They provoke the development of a syndrome of exacerbation of chronic infection (inflammatory diseases of the oral cavity and jaws, tonsillitis, etc.), food allergies, strong odors, and traumatic brain injury.

Features of clinical manifestations

Rossolimo-Melkerson-Rosenthal syndrome is recurrent swelling of the lips and other parts of the face or body parts in combination with recurrent paralysis of the facial nerve and phenomena of granulomatous glossitis.

The first most common symptom is macrocheilia - non-inflammatory swelling of the red border, mucous membrane and skin of the lips. The upper lip sometimes increases in volume by 2-3 times. Swelling can also be localized in the cheeks, eyelids, on the mucous membrane of the oral cavity, on the skin of the torso and limbs.

One of the main symptoms (the second most important) is damage to the facial nerve in the form of peripheral paralysis or paresis, which is observed in half of the patients. Recurrent neuropathy of the facial nerve can be explained by periodically occurring local swelling of the facial tissues, which, by squeezing this nerve, first causes its functional impairment, and then an organic defect.

Damage to the facial nerve occurs after it exits the stylomastoid foramen. In rare cases, the trigeminal, oculomotor, and glossopharyngeal nerves may be involved in the process.

The third sign of the syndrome, a folded tongue, is regarded as a developmental anomaly in this group of patients. Much more often, granulomatous glossitis develops in patients with Rossolimo-Melkerson-Rosenthal syndrome. Against the background of folding of the tongue, swelling develops, which leads to difficulty speaking and eating.

In most patients, the swelling is persistent and lasts from several months to several years. Often there are mental changes of the depressive type.

Treatment

In the acute period, rest, bowel cleansing, and a dairy-vegetable diet are necessary. Disensitizing therapy is prescribed (diphenhydramine, suprastin, tavegil), for the purpose of dehydration - furosemide, veroshpiron, triampur, drugs that reduce parasympathetic reactions (atropine, belloid) and increase sympathetic ones (ephedrine). Courses of glucocorticoids, vitamins B1, B6, and physiotherapy (diadynamic currents, ultrasound, acupuncture, UHF, intranasal electrophoresis with diphenhydramine) are required.

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.