Behçet’s Disease – Symptoms and Treatment

Behçet’s Disease – Introduction:

Behçet’s disease is a chronic systemic vasculitis with effects on multiple organs, and its exact causes are not fully understood. It is characterized by three main symptoms: ocular inflammation, painful mouth ulcers, and genital ulcers.

The disease is named after the Turkish dermatologist Hulusi Behçet, who in 1937 unified the main symptoms of the disease. Its prevalence is higher in countries that were part of the ancient Silk Road: Marco Polo’s trade route from the East to Turkey to the Mediterranean Sea.

Prevalence of Behçet’s Disease:
Currently, the prevalence of Behçet’s disease in European countries is one case per 300,000 people, while in Turkey and Japan, it reaches one case per 10,000 individuals. The disease occurs equally in men and women, but its impact is more severe in men. The peak onset coincides with the third decade of life. Behçet’s disease rarely develops in childhood or after the age of forty-five. Familial cases are uncommon. Deaths associated with the disease may result from central nervous system involvement, rupture of aneurysms, and erosion or perforation of the intestinal wall.

Causes of Behçet’s Disease:
The causes of the disease are unknown. According to some hypotheses, it could be triggered by viral or bacterial infections, leading to an atypical immune response in individuals with genetic predispositions. In some cases, the disease is associated with the presence of the HLA-B51 antigen. However, this marker is not considered a diagnostic criterion and does not determine the prognosis of the disease.

Symptoms of Behçet’s Disease Include:

1. Mouth Ulcers: The main symptom, where ulcers appear on the mouth mucosa, lips, gums, cheeks, and tongue. These ulcers are usually small (less than 1 cm in diameter), multiple (3 to 10 at a time), and recurrent before healing within 1-3 weeks. This symptom is present in almost 100% of patients.
2. Painful Genital Ulcers: More common in women, affecting the genital lips, and in men, the scrotum area. After healing, they may leave small scars. About 5% of men suffer from epididymitis (non-infectious inflammation of the epididymis) that may lead to infertility.
3. Skin Involvement: Includes nodular formation, acne-like rash, skin redness and pustule formation, among others.
4. Skin Hypersensitivity (Pathergy): A diagnostic test based on this feature, where skin puncture with a needle tip leads to the formation of a center of redness and inflammation.
5. Eye Involvement: Ocular inflammation is more common in young individuals, presenting with inflammatory cell accumulation in the anterior eye membrane (hypopyon) or progressing to recurrent acute inflammation of all parts of the vascular membrane of the eye and vitreous humor involvement. It may also affect the anterior (anterior uveitis or lens inflammation) or posterior (posterior uveitis or choroiditis) eye parts, and in rare cases, pseudoiritis may occur.
6. Joint Problems: Joint inflammation may occur as a manifestation of the disease, with inflammation occurring in knee, ankle, wrist, and elbow joints. Inflammatory fluid may accumulate in the joints, leading to pain and limited movement.
7. Cardiac and Vascular Effects: Problems such as myocarditis, meningitis, and coronary artery inflammation may occur. Signs of heart involvement include chest pain and shortness of breath.

Other Symptoms of Behçet’s Disease:

1. Central Nervous System Disorders: In severe cases, infections such as non-infectious meningitis (with symptoms such as headache and stiff neck), encephalitis (with symptoms such as fever, altered consciousness, and seizures), and effects on the brainstem may occur. In women, benign cerebral vasculitis syndrome may sometimes occur, causing severe headaches.
2. Psychological Symptoms: Including anxiety disorders, depression, memory, and concentration disorders.
3. Gastrointestinal Effects: Ulcers may appear in the rectal and colonic mucosa. Affected individuals may experience abdominal pain, gas accumulation, and may develop constipation or diarrhea. In residents of remote Eastern regions, the incidence of gastrointestinal involvement is higher than in countries around the Mediterranean Sea basin. This may be associated with a higher rate of HLA-B51 antigen detection in them.
4. Renal Effects: Direct kidney involvement is rare, but glomerular inflammation (inflammation of the blood capillary areas of the kidneys due to autoimmune inflammation) may develop in some cases. However, when urinary protein excretion increases rapidly with elevated blood protein levels, severe kidney failure may result.
5. Pulmonary Effects: Lung involvement rarely occurs and usually occurs when large blood vessels are ruptured, leading to coughing up blood due to the rupture of weak vessels, which can be fatal.

Behçet’s Disease: Mechanism and Classification

The mechanism of Behçet’s disease is not fully understood. It is not a conventional autoimmune disease, as specific antibodies triggering an atypical immune response have not been discovered yet. However, in this disease, numerous molecules and structures that provoke and sustain inflammation are formed.

During the inflammatory flare-ups (clusters of blood and lymph), activated CD4 T cells and macrophages (cells capable of engulfing bacteria) are found. Disease activity is accompanied by excessive cytokine production (proteins responsible for cell interaction) such as IL-1, IL-6, IL-10, IL-12, TNF, and others. Elevated levels of markers of inner layer activation of blood vessels in serum, which are associated with the development of comprehensive vascular damage, are characteristic.

The morphological pattern of Behçet’s disease is vasculitis. Examination of affected parts of blood vessels reveals lymphocyte and plasma cell leakage, congestion, proliferation of the inner layer, damage to the elastic membrane of blood vessels, and degradation of the middle envelope.

Classification and Stages of Behçet’s Disease:
Regarding stages:
The disease does not exhibit specific stages. The number and severity of clinical symptoms can vary at different times during the course of the disease. The disease is characterized by alternating periods of exacerbation and remission.

Japanese criteria for Behçet’s disease:
Developed in 1984, the Japanese criteria for Behçet’s disease are considered classical and include major and minor criteria.

Major criteria:

1. Recurrent oral ulcers (covered with a thin white layer).
2. Skin lesions: nodular dermatitis, superficial venous thrombosis, adjacent hair inflammation, acne-like rash, skin hypersensitivity.
3. Eye diseases: lens and vitreous inflammation, retinal and choroidal inflammation, vitreous or retinal inflammation with true retinal attacks or choroidal inflammation.
4. Genital ulcers.

Minor criteria:

1. Arthritis without deformities.
2. Gastrointestinal involvement: ulcers in the deep section of the intestines.
3. Folliculitis (inflammation of the tail of the epididymis).
4. Vascular disorders.
5. Central nervous system involvement.

Disease classification:

• Complete: Complete presence of all four major symptoms.
• Incomplete:
• Three major symptoms.
• Two major + two minor.
• Typical ocular involvement + one major or two minor.
• Probable:
• Two major.
• One major + two minor.

Degree of activity and severity:
Activity is determined based on Behçet’s disease activity index, calculated based on the presence of disease symptoms during the last four weeks before the doctor’s visit. Severity (mild, moderate, severe) is determined based on the type of organ damage. Severe severity is defined when there is retinal damage in the eye with vascular involvement, vessel thrombosis, and there is a threat of intestinal wall rupture or actual rupture.

Complications of Behçet’s Disease:

Cardiac Involvement:

• This can lead to heart attacks and cardiac rhythm disturbances.

Recurrent Venous Thrombosis in Extremities:

• Recurrent venous thrombosis can lead to congestion phenomena. Arterial thrombosis causes acute disruption of blood flow. Arterial vessel ruptures (aneurysmal dilations) are extremely dangerous, as they can result in fatal outcomes.

Intestinal Ulcers:

• Intestinal ulcers may lead to intestinal wall rupture and the development of peritonitis. In cases of central nervous system involvement, thrombosis in the venous sinuses of the dura mater is serious. When the eyes are affected, it can lead to vision deterioration, even complete blindness.

Diagnosis of Behçet’s Disease:

1. Collection of complaints and medical history: The doctor will inquire about the patient’s nationality and their parents’ nationality (the disease commonly occurs in Turks, Caucasians, and Far Easterners) and whether there are similar symptoms in their relatives – mother, father, siblings. It is also important to obtain information about previous episodes of recurrent oral ulcers, genital ulcers, post-pubertal acneiform rash, eye involvement with deteriorating vision, vascular thrombosis, joint pains.
2. Physical examination: Includes external examination, listening to the heart and lungs, abdominal palpation, and joint assessment. If necessary, examination by other specialist doctors: neurologist for neurological assessment, gynecologist and urologist, ophthalmologist, vascular surgeon, and others.
3. Laboratory diagnosis: There are no specific laboratory markers for Behçet’s disease. There may be a mild increase in erythrocyte sedimentation rate and C-reactive protein, and in serum, elevated levels of immunoglobulins may be detected, and in some cases, HLA-B51 antigen may be present. The main diagnostic evidence is the appearance of clinical symptoms.
4. Use of modified Behçet’s criteria: Since 2014, modified Behçet’s criteria have been used, where points are assigned for each sign, such as oral ulcers (2 points), genital ulcers (2 points), eye involvement (2 points), skin involvement (1 point), neurological involvement (1 point), vascular involvement (1 point), and positive skin prick test (1 point). If the total points are more than 4, Behçet’s disease can be diagnosed.

Differential diagnosis:

In some cases, there may be questions about differential diagnosis. For example, in Behçet’s syndrome with uveitis and arthritis (uveitis with inflammatory eye involvement and asymmetrical arthritis), ulcers may appear on the oral and genital mucosa, but they are painless and do not recur. Eye involvement is more common such as conjunctivitis. In contrast to Behçet’s disease, this syndrome does not typically include vasculitis, thrombosis, and central nervous system involvement.
There are some common features with Behçet’s disease in non-specific ulcerative colitis (superficial mouth ulcers, joint inflammation, nodular skin redness, anterior eye inflammation), but at the same time, the absence of genital ulcers and posterior eye effects. Oral ulcers in ulcerative colitis do not have the same severe recurrent nature. When colonoscopy is performed on patients with Behçet’s disease, the ulcers in the intestines are surrounded by non-inflammatory mucosa, whereas mucosal inflammation is seen around the ulcerations in ulcerative colitis.
In the case of ordinary ulcerative stomatitis, unlike Behçet’s disease, there are no elevations in C-reactive protein, immunoglobulins, or accelerated sedimentation rate. Also, there is no effect on other organs or systems in the body.

Treatment of Behçet’s Disease:

The goal of Behçet’s disease treatment is to achieve remission (relief of symptoms), as autoimmune diseases persist throughout life. Treatment primarily targets the causes (directed towards the mechanisms of disease occurrence), but symptomatic treatment may also be necessary.

• Oral ulcers respond well to colchicine treatment at doses up to 1.5 mg daily. In rare cases, treatment with another anti-inflammatory such as azathioprine may be directed.
• Creams containing corticosteroids are used for skin damage. Methotrexate, sulfasalazine, and leflunomide may be used for joint inflammation.
• Eye damage is treated with corticosteroids, some cytostatic immunosuppressants (such as azathioprine and cyclosporine A), and interferon-alpha.
• Corticosteroids, cyclophosphamide, cyclosporine A, azathioprine, mycophenolate mofetil, methotrexate, and interferon-alpha may be effective in cases of central nervous system damage.
• Biologic genetic medications are also used in cases of severe organ damage, such as tumor necrosis factor inhibitors (infliximab, adalimumab, etanercept), IL6 inhibitors (tocilizumab), and IL1 inhibitors (canakinumab).

In case of emergency contact:
Emergency medical services should be called if any of the following symptoms occur:

• Coughing up blood, difficulty breathing, pain, swelling, and change in skin color in the leg or arm (signs of thrombosis).
• Loss of consciousness, vision disturbances or double vision, weakness in the arm or leg, sudden severe headache, memory loss, and speech disturbances (signs of neurological disorder).
• Severe abdominal pain (may indicate a thrombosis or intestinal tear).
• Black stool and general weakness (possible gastrointestinal bleeding).
• Loss of vision (retinal thrombosis).
• Severe chest pain (thrombosis, cardiovascular problems).

In the hospital:
Treatment methods in the hospital will depend on the main symptoms.

• In case of recurrent thrombosis, intravenous injections of steroids and cyclophosphamide (cytostatic antitumor) may be possible. In case of occurring thrombosis, anticoagulants are prescribed. Anticoagulants should be used with extreme caution and according to precise indications, as they can cause bleeding from silent arterial ruptures.
• Surgical treatment may be required when there is dilation of blood vessels. In cases of uncontrolled bleeding, arterial thrombosis skin infarction is performed – injection of substances resembling silver or other specialized materials into the separated cystic thrombosis. This creates conditions for excluding the dangerous segment of the artery from blood flow, reducing the risk of its rupture. Corticosteroids and cyclophosphamide are necessary for the treatment of arterial dissection.
• In case of deep vein thrombosis, corticosteroids, azathioprine, cyclophosphamide, and cyclosporine A are used.
• In case of bowel damage, surgical methods may be applied.
• In case of neurological manifestations, such as hemiplegia or spinal cord inflammation or meningeal symptoms, treatment with corticosteroids, cytostatics (cyclophosphamide, azathioprine, mycofenolate mofetil, methotrexate), and genetically modified biological drugs – tumor necrosis factor-α inhibitors (infliximab, adalimumab, etanercept) are prescribed.
• Genetic biological drugs are also used in cases of severe organ damage, such as tumor necrosis factor inhibitors (infliximab), IL6 inhibitors (tocilizumab), and IL1 inhibitors (canakinumab).

Prognosis:

• The outcome depends on the nature of the damage to the organs and systems. If the process is limited to mucosal ulceration in the mouth and genitalia, the course of the disease is assessed as mild. Male gender and disease onset before the age of 25 years are negative prognostic factors.
• Poor control of eye damage can lead to vision loss. The appearance of arterial blood vessels, intestinal disorders, and central nervous system involvement are unfavorable prognostic factors.
• The disease is characterized by intermittent course with periods of exacerbation and improvement, but it usually does not lead to early death. Serious arterial and neurological disorders occur only in a small proportion of patients.

Prevention:

• There is no primary prevention of the disease. Secondary prevention involves following treatment recommendations and regular visits to the doctor. Special attention should be paid to ophthalmological examination in case of eye damage and neurological monitoring by the neurologist to control cases of central nervous system damage.

References:

• Rheumatology. Russian Clinical Recommendations. Edited by E.L. Nasonov, Moscow: GEOTAR-media, 2019. 464 p.
• Alekberova, Z.S. Behcet’s Disease (lecture) // Scientific and Practical Rheumatology, 2013, 51(1), pp. 52-58.
• Handbook of Rheumatology. A. Hakim, G. Clunie, I. Hack; translated from English by N.I. Tatarkina; edited by O.M. Lesnyak. Moscow: GEOTAR-media, 2010. 560 p.