Hospital Medicine

Behcet's syndrome

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Behcet's syndrome

I. What every physician needs to know.

Behcet's syndrome (BS) is a rare, chronic, relapsing multisystem vasculitis affecting arteries and veins of all sizes. Recurrent, painful mucocutaneous ulcers are the hallmark of the disease and often precede other manifestations. Other systems involved include ocular, skin, gastrointestinal tract, pulmonary, vascular, nervous system, and musculoskeletal. Exacerbations and remissions recur with varying interval ranging from 1 week to 2 years. Vascular, ocular and neurologic involvement are associated with greater morbidity and mortality with aneurysm rupture being the main cause of death in patients with BS. BS is prevalent in countries along the Silk Road extending from Eastern Asia to the Mediterranean region. Highest prevalence is in Turkey where it was first reported.

Pathogenesis is unknown but genetic predisposition and environmental factors including infection are all thought to play a role.

II. Diagnostic Confirmation: Are you sure your patient has Behcet's syndrome?

It’s a clinical diagnosis. Numerous classification/diagnostic clinical criteria (over 17) exist. Two international widely used criteria include:

  • International Study Group for Behcet’s Disease criteria (ISG criteria) depends on presence of recurrent oral ulcers (OU), plus any two of recurrent genital ulcers (GU), typical eye lesions, typical skin lesions or a positive skin pathergy test (SPT).

  • International Criteria for Behcet’s Disease (ICBD), created in 2006 and revised in 2013, is new criteria in which OU, GU and ocular manifestations are assigned 2 points while others (skin, neurologic, vascular and positive SPT) are assigned 1 point with 4 points or greater being diagnostic of BS. Using an international cohort of patients, ICBD was found to have a sensitivity of 96.1% and a specificity of 88.7%.

  • Studies comparing the two clinical criteria suggest the revised ICBD criteria is more sensitive and accurate but less specific than the ISG.

A. History Part I: Pattern Recognition:

KEY SYMPTOMS/SIGNS

Oral ulcer (OU)

  • Hallmark of the disease occurring in 97-100% patients and often preceding diagnosis by years.

  • Typically, painful, round or oval with well-defined, rolled border and a grayish yellow necrotic base. Lesions resolve spontaneously over 1 or 4 weeks and recur with variable intervals ranging from days to months.

  • Commonly occur on lips, buccal mucosa, tongue and less commonly palate, pharynx, and tonsils.

Genital ulcers (GU)

  • Also common (over 70% of cases) and similar in appearance to OU but larger and deeper. Unlike OU, they scar, heal more slowly, and recur less frequently.

  • Most common sites are on the vulva and vagina in women and on the scrotum in men. Groin, perianal and perineal ulcers can be seen in both sexes.

Other less common mucous membrane manifestations include anal and conjunctival ulcers.

Skin manifestations

  • Seen in 75% of patients.

  • Erythema Nodosum(EN)-like lesions involve painful, erythematous nodule on peritibial tissue as well as face, neck, forearms and buttocks areas that resolve without ulceration in 2-3 weeks.

  • Papulopustular lesions are sterile, acne-like lesions on erythematous base commonly found on trunk, buttocks and lower limbs.

  • Superficial thrombophlebitis.

  • Pathergy reaction, hyperreactivty of skin to minor trauma resulting in sterile papule or pustule in 24 to 48 hours, is also seen.

Ocular

  • Occurs in 30-70% of patients.

  • Includes panuveitis (most frequent), anterior uveitis, posterior uveitis and retinal vasculitis.

  • Involvement and damage tends to occur early in the disease course.

Musculoskeletal

  • Occurs in up to 50% of patients.

  • Typically, non-erosive, monoarticular or oligoarticular arthritis of medium and large joints such as keens, wrists and ankles.

Neurological manifestations

  • Neuro-Behcet’s disease is rare and often presents as meningoencephalitis or vascular thrombotic events.

  • Tends to occur late in the disease course but can cause severe morbidity and mortality.

Gastrointestinal

  • GI manifestations (abdominal pain, nausea, hematemesis, dysphagia and diarrhea) are seen in 3-50% of cases.

  • Mainly due to mucous inflammation and ulceration which can occur at any part of the digestive tract.

  • Ileocecal involvement is common.

Vascular involvement

  • Less common (about 25% of cases).

  • Can involve arteries and veins of all size and may present as arterial or venous thrombosis, aneurysms, pulse weakness, or superficial phlebitis. Sudden death in BS is most often from a ruptured aortic or arterial aneurysm.

Pulmonary manifestations

  • Rare but associated with high mortality.

  • Includes pulmonary embolism, fibrosis, pleurisy, vasculitis, and infection.

Cardiac manifestations

  • Also rare and includes pericarditis, endocarditis, intracardiac thrombosis, myocardial infarction, endomyocardial fibrosis and myocardial aneurysm.

B. History Part 2: Prevalence:

Geography

  • More endemic in Turkey, Iraq, Iran, Korea, and Japan. Europeans living between the latitudes of 30°N and 45°N are more likely to develop BS than their Northern European counterparts.

Sex

  • Sex distribution is roughly equal with some exceptions (more common in men in the ancient Silk Road countries but more common in women in Northern Europe and the United States).

Age

  • Onset is 2nd to 4th decade of life.

Genetics

Genetics seems to play a role in the development of BS. The class I human leukocyte antigen (HLA) genotype B5 and its subclass B51 allele on chromosome 6p21 has been linked to the development of BS in those living along the Silk Road. HLA-B51 is more common in patients with severe morbidity from BS from posterior uveitis or central nervous system (CNS) involvement.

C. History Part 3: Competing diagnoses that can mimic disease Behcet's syndrome.

Crohn's disease

Ulcers in BS are usually round or oval compared to the ulcers in Crohn's disease, which are longitudinal. Distribution is focal in BS compared to a segmental or diffuse distribution in Crohn's disease. Granulomas are not formed in BS.

Reactive Arthritis (formerly called Reiter syndrome)

Urethritis does not commonly occur in BS.

Ankylosing spondylitis

Sclerosis causing obliteration of joints is rarely seen in BS.

Lupus erythematosus

There are no pathognomonic laboratory tests for BS.

Herpes simplex virus

Causes oral and esophageal ulcers (endoscopic brushing, biopsy and culture can differentiate between BS and herpes simplex virus (HSV) esophagitis).

D. Physical Examination Findings.

  • Skin: erythematous tender nodules of different sizes on legs (consistent with erythema nodosum), chronic postphlebitic edema and trophic changes on legs and superficial thrombophlebitis.

  • Eyes: hypopyon.

  • Mouth: round or oval ulcers on lips, gingiva, buccal mucosa, and tongue with a whitish/yellowish pseudomembrane.

  • Extremities: swelling and erythema of knee, ankle, elbow, and/or wrist.

  • Genital: aphthous ulcers on scrotum or vulva.

E. What diagnostic tests should be performed?

A thorough physical exam looking for oral aphthous ulcers, genital ulcers, ocular lesions, skin manifestations, and vascular lesions should be performed.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

You can perform a pathergy test. Use a number 25 needle to prick your patient's skin to a depth of 5mm. If there is 2mm erythema in 24-48 hours, the test is positive.

No laboratory studies are needed.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

In general, imaging studies are not helpful in diagnosing BS. However, if patients have pulmonary complaints, computed tomography (CT) scan of the chest may help elucidate disease related to BS. If patients present with neurologic manifestations, magnetic resonance imaging (MRI) may help to detect focal lesions related to NB. In patients with abdominal pain, diarrhea or constipation, a double-contrast barium x-ray could help detect ileocecal ulcers.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Erythrocyte sedimentation rate and C-reactive protein are both non-specific.

III. Default Management.

Treatment varies depending on which organs are involved. Treatment recommendation is based on limited data due to sparsity of recent randomized, placebo controlled, trials.

Treatment by organ system.

Mucocutaneous manifestations:

  • Topical class I or II steroids may help relieve pain.

  • Topical sucralfate mouthwash 1 g/5mL 4 times a day has been shown to reduce pain and help healing.

  • Intralesional glucocorticoids can be used for large ulcers.

  • Systemic glucocorticoids may be used when ulcers are refractory to topical treatment or colchicine (can start with prednisone 15 mg/day, taper to 10 mg/day after 1 week).

  • Azathioprine 2.5 mg/kg per day should be tried if daily prednisone dose of more than 10 mg is required.

  • Anti-tumor necrosis factor (Anti-TNF) alpha agents (infliximab or etanercept) may be tried as an alternative to azathioprine.

  • Interferon alfa is another alternative.

If a medium-vessel vasculitis is confirmed, more aggressive treatment is recommended (prednisone 40-60 mg by mouth daily in addition to azathioprine 50 mg by mouth daily).

Arthritis

  • Colchicine has been shown to be helpful at a dose of 0.6 mg by mouth 2-3 times a day.

  • Non-steroidal anti-inflammatory drugs (NSAIDs) may help.

  • If colchicine doesn't help, you can try prednisone 10 mg by mouth daily for a short time.

  • Alternatively, azathioprine may be used instead of glucocorticoids.

Ocular disease

  • Anterior uveitis: topical glucocorticoids and a dilating drop such as scopolamine 0.25% or cyclopentolate 1%.

  • Posterior uveitis: high-dose glucocorticoid (prednisone 1 mg/kg per day for 1 month then taper as tolerated) and azathioprine. Immunosuppressive therapy is continued for at least 18-24 months.

Neurologic disease

  • Aseptic meningitis: high doses of glucocorticoids (1 mg/kg per day).

Gastrointestinal disease

  • Prednisone 0.5-1 mg/kg daily and azathioprine 2.5 mg/kg per day.

  • Infliximab 3-5 mg/kg at 0, 2 and 6 weeks, followed by 5 mg/kg every 8 weeks.

Renal disease

  • Secondary (AA) amyloidosis: colchicine 1-1.2 mg by mouth daily.

Vascular manifestations

  • Large artery disease: high-dose glucocorticoids and cyclophosphamide.

  • Venous thrombosis: anticoagulation and rarely local thrombolysis.

Treatment by drugs:

Corticosteroids (CS)

  • Topics CS fist line for those with mild disease. It is used to treat oral and genital ulcerations.

  • Systemic CS recommended for those with moderate to severe disease with other organ involvement and can be used in combination with other immunosuppressive drugs.

Colchicine

  • Used as first line for mucocutaneous manifestations.

Azathioprine

  • One of the more commonly used immunosuppressive medications for BS. Shown to be beneficial in those with OU, GU, ocular disease and arthritis in a placebo-controlled trial.

Thalidomine

  • Effective in treating mucocutaneous lesions.

Cyclosporine

  • Commonly used for uveitis associate with BS but can cause neurotoxicity or accelerate development of CNS symptoms.

Cyclophosphamide

  • Not enough evidence supporting its use but used in those with severe, life-threatening manifestations (major vessel, pulmonary artery, CNS).

Interferon-alpha

  • Used in mucocutaneous disease, arthritis, ocular uveitis.

Tumor necrosis factor-alpha inhibitors (TNF-a)

  • Observational studies showed Infliximab to be effective in reducing frequency of uveitis attacks, refractory macular edema, gastrointestinal disease. Other drugs in this class can also be used to treat manifestation of BS.

Rituximab

  • Used in combination with other agents to treat retinal vasculitis and edema resistant to cytotoxic treatment.

A. Immediate management.

If a patient is hospitalized with BS, the disease is likely severe with neurologic manifestations, sight-threatening ocular manifestations or painful oral ulcers causing difficulty swallowing. Severe disease needs treatment with high-dose glucocorticoids and azathioprine.

B. Physical Examination Tips to Guide Management.

Improvement/lack of improvement in signs or symptoms should guide management.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

None.

D. Long-term management.

The patient will need to follow up with a rheumatologist as an outpatient. Depending on what organs are involved, the patient may need to follow up with neurology, ophthalmology, gastroenterology, or nephrology.

E. Common Pitfalls and Side-Effects of Management.

N/A

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

Dose adjust azathioprine in renal insufficiency. If a patient has severe renal impairment use high-dose steroids cautiously.

B. Liver Insufficiency.

Monitor liver function tests (LFTs) closely if using azathioprine. If a patient has severe hepatic impairment, use high-dose steroids cautiously.

C. Systolic and Diastolic Heart Failure.

High-dose steroids may be used but the patient's heart failure status must be monitored closely since steroids can exacerbate heart failure. Dietary salt restriction is recommended.

D. Coronary Artery Disease or Peripheral Vascular Disease.

Patients who have had a recent myocardial infarction should avoid glucocorticoids if possible because there may be an association between glucocorticoids and left ventricular free-wall rupture.

E. Diabetes or other Endocrine issues.

Blood sugars will need to be monitored closely if the patient is diabetic and requires high-dose steroids. The patient's insulin regimen or oral anti-diabetic regimen or diet may need to be changed.

In patients with osteoporosis, corticosteroids should only be used if treatment is life saving. Patients with osteopenia or osteoporosis who receive high-dose steroids will need calcium/vitamin D supplementation and bisphosphonate therapy (first line) or calcitonin (second line).

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

Azathioprine and corticosteroids should be used with caution in patients who are already immunosuppressed.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

Patients with peptic ulcer disease should take antacids between meals if they are started on high-dose corticosteroids.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

High-dose steroids can cause delirium and should therefore be used with caution in patients who have dementia and are already at high risk for developing delirium.

V. Transitions of Care.

A. Sign-out Considerations While Hospitalized.

N/A

B. Anticipated Length of Stay.

The typical length of stay is 1-3 days.

C. When is the Patient Ready for Discharge?

Assuming any acute neurological or ocular manifestations have improved, the patient is ready for discharge when he/she is able to swallow liquids.

D. Arranging for Clinic Follow-up.

The patient will need to follow up with a rheumatologist as an outpatient. Depending on what organs are involved, the patient may need to follow up with neurology, ophthalmology, gastroenterology, or nephrology.

1. When should clinic follow up be arranged and with whom?

The patient will need to follow up with a rheumatologist within 1-2 weeks. Depending on other clinical manifestations, the patient should follow up with neurology, ophthalmology, gastroenterology, or nephrology within 1-2 weeks.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

N/A

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

N/A

E. Placement Considerations.

The patient will likely be discharged home and will not need placement.

F. Prognosis and Patient Counseling.

Prognosis is excellent.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

None

VII. What's the evidence?

Rokutanda. "Update on the diagnosis and management of Behçet’s disease". https://dx.doi.org/10.2147/OARRR.S46644.

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