Diagnosis of Behcet’s Disease: A Comprehensive Guide for Clinicians

Introduction

Behcet’s disease (BD), also known as Behcet’s syndrome and malignant aphthosis, is a chronic, relapsing, multisystemic, auto-inflammatory vasculitis of unknown etiology. First described in 1937 by Turkish dermatologist Hulusi Behçet, it is characterized by a triad of recurrent oral ulcers, genital ulcers, and uveitis. However, BD is a systemic condition that can affect various organs, including the skin, eyes, joints, blood vessels, nervous system, and gastrointestinal tract. Accurate and timely diagnosis of Behcet’s is crucial for effective management and preventing severe complications. This article aims to provide a detailed overview of the diagnostic process for Behcet’s disease, focusing on clinical evaluation, diagnostic criteria, differential diagnosis, and the importance of an interprofessional approach.

Etiology of Behcet’s Disease

The precise cause of Behcet’s disease remains elusive, but current understanding points towards a complex interplay of genetic predisposition and environmental triggers. It is not considered a hereditary disease in the Mendelian sense, but genetic factors significantly increase susceptibility.

Genetic Factors

The strongest genetic association is with HLA-B51/B5, a class I major histocompatibility complex (MHC) antigen. Individuals carrying HLA-B51/B5 have a significantly higher risk of developing BD compared to non-carriers. This genetic marker is particularly prevalent in populations along the ancient “Silk Route,” which correlates with the higher incidence of Behcet’s disease in these regions. Other genes, including those related to tumor necrosis factor (TNF), heat shock proteins, and MHC class I chain-related molecules, have been implicated, but their exact roles are still under investigation.

Environmental Factors

Environmental factors, particularly infectious agents, are suspected to play a role in triggering the auto-inflammatory response in genetically predisposed individuals. Streptococcus sanguinis antigens have been proposed as potential triggers, suggesting a possible link between bacterial hypersensitivity and BD. Other infectious agents like Staphylococcus aureus, Herpes simplex virus type 1, and Prevotella species have also been investigated, but definitive causal links are yet to be established. The prevailing hypothesis suggests that exposure to an infectious or environmental agent initiates an abnormal immune response in genetically susceptible individuals, leading to the characteristic inflammation and vasculitis of Behcet’s disease.

Epidemiology of Behcet’s Disease

Behcet’s disease exhibits a distinct geographical distribution, with higher prevalence along the “Silk Route,” stretching from East Asia to the Mediterranean region. Turkey has the highest reported prevalence, with approximately 420 cases per 100,000 population. In contrast, prevalence rates are considerably lower in North America and Northern Europe, such as 5.2 per 100,000 in the United States.

Age and Sex Distribution

BD typically manifests in young adults, with onset most common between 20 and 40 years of age. Juvenile-onset BD, while less frequent, does occur. The sex distribution varies geographically. While overall, both genders are affected, a male predominance is noted in Arab populations, whereas female predominance is observed in Korea, China, the United States, and parts of Northern Europe. Disease course tends to be more severe in males and individuals with younger onset.

Familial Occurrence

Most cases of Behcet’s disease are sporadic. However, familial clustering has been reported, indicating a genetic component. Genetic anticipation, where the disease presents at an earlier age in successive generations, has also been described, further supporting the role of genetic factors.

Pathophysiology of Behcet’s Disease

Behcet’s disease is fundamentally an auto-inflammatory vasculitis, affecting blood vessels of all types and sizes, both arteries and veins. Unlike some other forms of vasculitis, BD is characterized by a lack of necrotizing vasculitis and giant cell formation. A distinctive feature of BD is the involvement of venules and the potential formation of pulmonary and arterial aneurysms. Notably, specific autoantibodies, commonly seen in other autoimmune diseases like systemic lupus erythematosus, are generally absent in Behcet’s disease.

Immune System Involvement

Cell-mediated immunity plays a central role in the pathogenesis of BD. Activation of type 1 helper T (Th1) cells leads to elevated levels of circulating T-lymphocytes, contributing to the diverse clinical manifestations. Pro-inflammatory cytokines, including IL-1, IL-8, IL-12, IL-17, IL-37, and TNF-alpha, are upregulated in BD and are believed to drive the inflammatory processes. These cytokines may also serve as markers of disease activity and severity.

Increased activation of macrophages, neutrophil chemotaxis, and phagocytosis are observed in BD lesions. Mucocutaneous lesions, such as oral aphthae, skin pustules, and erythema nodosum, are thought to arise from excessive neutrophil activation, resulting in a neutrophilic vascular reaction and subsequent tissue damage. Circulating immune complexes also participate in this neutrophilic vascular reaction. Endothelial cell dysfunction and anti-endothelial cell antibodies are also implicated in the pathogenesis of Behcet’s disease, contributing to the vasculitic process.

Histopathology of Behcet’s Disease

Histopathological examination of tissue biopsies in Behcet’s disease reveals vasculitis and thrombosis as key features. Biopsies from mucocutaneous lesions typically demonstrate a neutrophil-predominant inflammatory reaction characterized by endothelial swelling, red blood cell extravasation, and leukocytoclastic vasculitis with fibrinoid necrosis of blood vessel walls. The presence of lymphocytic vasculitis suggests older lesions, while a neutrophilic vascular reaction is considered the hallmark acute histopathological finding. Vasculitis affecting the vasa vasorum can lead to aneurysm formation in larger arteries. Synovial fluid analysis in BD arthritis shows neutrophil-predominant leukocytosis, with cell counts ranging widely from 300 to over 30,000 cells/mm^3.

Clinical Presentation and Diagnostic Clues for Behcet’s Disease

Diagnosis of Behcet’s is primarily clinical, relying on the recognition of a constellation of characteristic signs and symptoms. While mucocutaneous lesions are the most common features, the most serious manifestations involve the eyes, large vessels, and nervous system.

Mucocutaneous Manifestations

• Oral Aphthae: Recurrent oral ulcers are the most frequent manifestation, occurring in 97% to 99% of BD patients and often being the initial symptom. These ulcers are typically painful, recurrent, and multiple, affecting the soft palate, hard palate, buccal mucosa, tongue, gingiva, lips, and tonsils. They usually heal without scarring in over 90% of cases.

• Genital Aphthae: Genital ulcers are seen in over 80% of BD patients. Similar to oral ulcers, they are recurrent, but in contrast, more than 70% heal with scarring. In males, they commonly occur on the scrotum (90%), and in females, on the vulva or vagina.

• Cutaneous Lesions: A variety of skin lesions are associated with BD.

  • Erythema nodosum-like lesions: These are common, particularly on the lower extremities. BD-related erythema nodosum shows a more vasculitic component compared to idiopathic erythema nodosum.
  • Superficial thrombophlebitis: Nodular lesions indicating superficial thrombophlebitis may occur and can be associated with deep vein thrombosis.
  • Acneiform lesions or pseudofolliculitis: These are common but non-specific and can be difficult to distinguish from ordinary acne.
  • Other less frequent cutaneous manifestations include pyoderma gangrenosum-like lesions, pustular vasculitic lesions, cutaneous small-vessel vasculitis, and Sweet syndrome-like lesions.

• Pathergy Test: A positive pathergy reaction is considered highly suggestive of Behcet’s disease. It is characterized by the formation of erythematous papules or pustules 24 to 48 hours after a sterile needle prick. The sensitivity of the pathergy test varies geographically, being more common in patients from Turkey and Japan (60% to 70%) and less frequent in those from Northern Europe or the United States.

Ocular Manifestations

Eye involvement occurs in over 50% of BD patients, more frequently in males and younger individuals. Ocular manifestations are usually not the initial symptom but typically develop within the first few years after diagnosis. Late-onset ocular involvement is rare if absent initially.

• Uveitis: The most common ocular manifestation is relapsing, chronic, bilateral uveitis affecting both anterior and posterior uveal tracts.
  • Anterior uveitis: Presents with erythema and photophobia.
  • Posterior uveitis: Can cause significant vision loss and is more sight-threatening.
  • Hypopyon: Uveitis with hypopyon (pus in the anterior chamber) is less common but particularly severe, often associated with severe retinal disease.
  • Retinal vasculitis: Retinal involvement, including retinal vasculitis, is a major cause of blindness in BD.
  • Conjunctivitis and isolated anterior uveitis are less common presentations.

Musculoskeletal Manifestations

Arthritis is seen in approximately 50% of BD patients. It is typically inflammatory, non-erosive, and non-deforming.

• Arthritis Pattern: Usually oligoarthritis, affecting a few joints, and can be symmetric or asymmetric. Polyarthritis and monoarthritis can also occur.
• Joint Distribution: Peripheral joints are predominantly involved, with knees being the most commonly affected, followed by ankles, wrists, and elbows. Spine involvement or sacroiliitis is not typical, helping to differentiate BD from HLA-B27-associated spondyloarthropathies.

Vascular Manifestations

Vascular involvement, a hallmark of Behcet’s disease, occurs in about 25% of patients, more frequently in males.

• Venous Thrombosis: Superficial and deep thrombophlebitis of the lower extremities are the most common vascular manifestations. Rarely, Budd-Chiari syndrome or vena cava obstruction may occur. Pulmonary embolism is uncommon due to the inflammatory nature of the thrombi, which tend to adhere tightly to the vessel wall.
• Arterial Vasculitis and Aneurysms: Arterial vasculitis can affect arteries of any size, leading to aneurysms or occlusions. Aortitis and vasculitis of the carotid, femoral, and popliteal arteries can occur.
• Pulmonary Artery Aneurysms: Pulmonary artery involvement with aneurysm formation is relatively unique to Behcet’s disease and is a leading cause of mortality.

Neurological Manifestations (Neuro-Behcet’s Disease)

Central nervous system (CNS) involvement occurs in 5% to 10% of BD patients.

• Parenchymal Neuro-Behcet’s: The most common form (80%), primarily affecting the brainstem, leading to cerebellar, pyramidal, and sensory signs and symptoms. Cerebrospinal fluid (CSF) analysis is usually sterile but may show elevated protein and/or cell count.
• Non-parenchymal Neuro-Behcet’s: Characterized by dural sinus thrombosis (20%), presenting with headaches and papilledema.
• Less common neurological manifestations include simultaneous parenchymal and non-parenchymal involvement, isolated cerebellar involvement, and cranial and peripheral nerve involvement.

Gastrointestinal Manifestations (Intestinal Behcet’s Disease)

Gastrointestinal involvement occurs due to mucosal ulcerations resembling orogenital aphthae, typically found in the terminal ileum, cecum, colon, and esophagus. Extensive ulcerations, particularly ileocecal lesions, can lead to perforation. It is important to differentiate intestinal Behcet’s from inflammatory bowel disease (IBD), as they can have overlapping features.

Other Systemic Manifestations

• Cardiac Involvement: Cardiac manifestations, including pericarditis, myocarditis, endocarditis, coronary artery vasculitis, and coronary aneurysms, have been reported.
• Renal Involvement: Renal involvement is rare but can include AA-amyloidosis and glomerulonephritis.
• Epididymitis: Inflammation of the epididymis can also occur.

Evaluation and Diagnostic Process for Behcet’s Disease

Diagnosis of Behcet’s disease is primarily based on clinical criteria, as there are no pathognomonic laboratory tests. Laboratory investigations are mainly used to exclude other conditions and assess organ involvement.

Clinical History and Physical Examination

A detailed clinical history focusing on recurrent oral and genital ulcers, ocular symptoms, skin lesions, joint pain, neurological symptoms, and gastrointestinal complaints is essential. A thorough physical examination should assess for mucocutaneous lesions, ocular findings (if possible, with ophthalmologic consultation), joint examination, and neurological assessment. The pathergy test, if performed, should be evaluated 24-48 hours after needle insertion.

Laboratory Investigations

• Non-specific Inflammatory Markers: Blood tests like complete blood count (CBC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) may show non-specific findings such as anemia of chronic disease, leukocytosis, and elevated inflammatory markers.
• Imaging Studies: Imaging is guided by organ involvement.
  • X-rays and Arthrocentesis: To evaluate arthritis.
  • CT-scan: To assess for bleeding, thrombosis, and ischemia in vascular or gastrointestinal involvement.
  • Angiography (CT angiography, MR angiography): To investigate aneurysms, particularly pulmonary artery aneurysms or large vessel involvement.
  • Lumbar puncture (CSF analysis): In cases of suspected neuro-Behcet’s disease to evaluate for CNS inflammation and rule out infections.
• Ophthalmologic Examination: A comprehensive ophthalmologic evaluation, including slit-lamp examination and fundoscopy, is crucial to assess for uveitis and retinal involvement.
• Skin Biopsy: Biopsy of cutaneous lesions can support the diagnosis by demonstrating characteristic histopathological features of vasculitis, but it is not pathognomonic for BD.

Diagnostic Criteria: The ITR-ICBD Criteria

Several classification criteria for Behcet’s disease have been developed to standardize diagnosis for research and clinical purposes. The most widely used and recently revised criteria are those from the International Team for the Revision of International Criteria for Behçet’s Disease (ITR-ICBD), revised in 2008. These criteria are point-based:

• Oral aphthosis: 1 point
• Genital aphthosis: 2 points
• Ocular lesions (uveitis, retinal vasculitis): 2 points
• Skin manifestations (pseudofolliculitis, skin aphthosis, erythema nodosum): 1 point
• Vascular lesions (phlebitis, large vein thrombosis, aneurysm, arterial thrombosis): 1 point
• Positive pathergy test: 1 point

A total score of three or more points is indicative of Behcet’s disease according to the ITR-ICBD criteria. It is important to note that these are classification criteria and should be used judiciously in clinical practice, alongside clinical judgment and exclusion of differential diagnoses. These criteria are designed to aid in diagnosis but do not replace clinical expertise.

Differential Diagnosis of Behcet’s Disease

Differential diagnosis of Behcet’s disease is broad due to its diverse clinical presentations. It is crucial to consider and exclude other conditions that can mimic BD, especially during the diagnostic process.

1. Inflammatory Bowel Disease (IBD): Both Crohn’s disease and ulcerative colitis can present with oral ulcers, uveitis, arthritis, erythema nodosum, and pyoderma gangrenosum, overlapping with BD. Intestinal ulcerations are seen in both conditions. Key differentiating features:

   • Sacroiliitis and axial inflammatory arthritis are more common in IBD, rare in BD.
   • Posterior uveitis and panuveitis are less typical in IBD.
   • Vascular inflammation, aneurysms, venous thrombosis, CNS involvement, and positive pathergy test are less characteristic of IBD.

2. Seronegative Arthritis (Reactive Arthritis): Reactive arthritis can also cause peripheral inflammatory arthritis, ocular inflammation, and skin lesions.

   • Posterior uveitis and panuveitis are less common in reactive arthritis.
   • Vascular or CNS involvement is rare in reactive arthritis.
   • Sacroiliitis and axial involvement are common in reactive arthritis, not in BD.
   • Urethritis, penile lesions (balanitis circinata), and conjunctivitis, features of reactive arthritis, are less typical in BD.

3. Systemic Lupus Erythematosus (SLE): SLE can have a similar multisystem presentation, affecting skin, joints, eyes, and even CNS and vessels.

   • Inflammatory thrombi are less typical in SLE.
   • SLE-specific autoantibodies (e.g., anti-dsDNA, anti-Smith) are present in SLE and absent in BD, aiding in differentiation.

4. Herpetic Infections (HSV, VZV): Oral and genital ulcers are prominent features of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Recurrent herpetic infections, especially atypical presentations, can mimic BD ulcers.

   • Viral culture or PCR from lesions can rule out herpetic infections.

5. Behçet’s-type disease induced by Interleukin-17 (IL-17) inhibitors: Paradoxically, some patients treated with IL-17 inhibitors (e.g., secukinumab) for other conditions like psoriasis can develop Behcet’s-like symptoms, including mucocutaneous lesions and uveitis. History of IL-17 inhibitor use is critical in these cases.

Other differential diagnoses to consider, depending on the predominant organ involvement, include:

• Sarcoidosis: Can cause uveitis, skin lesions, and neurological involvement.
• Other Systemic Vasculitides: Conditions like granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and polyarteritis nodosa (PAN) need to be considered, especially in cases with prominent vascular involvement.
• Relapsing Polychondritis: Can present with ocular inflammation and cartilage inflammation, but mucocutaneous ulcers are less typical.
• Multiple Sclerosis (MS): In cases of neuro-Behcet’s, MS should be considered, particularly in patients with CNS demyelinating events.

Prognosis and Complications of Behcet’s Disease

Behcet’s disease is a chronic condition without a cure, characterized by relapsing and remitting episodes. Prognosis varies, and while BD can be associated with significant morbidity and mortality, many patients experience periods of remission and improvement over time.

Prognostic Factors

• Male sex and younger age of onset: Associated with a poorer prognosis and higher mortality risk.
• Major organ involvement: Pulmonary artery aneurysms, neurological involvement, and gastrointestinal involvement are associated with higher mortality.
• Renal amyloidosis: Carries a poor prognosis.

Complications

• Blindness: A major complication of ocular involvement, particularly posterior uveitis and retinal vasculitis. Hypopyon-related uveitis is also a high-risk factor for vision loss.
• Vascular Complications: Rupture of pulmonary or peripheral aneurysms is a life-threatening complication.
• Neurological Sequelae: Neuro-Behcet’s can lead to permanent neurological deficits and disability.
• Gastrointestinal Perforation: Severe intestinal ulcerations can result in perforation and require surgical intervention.
• Pregnancy Complications: Increased risk of miscarriages due to placental vasculitis.

Despite these potential severe complications, more than 60% of patients experience remission after the initial years of active disease. Overall, with appropriate management, many patients achieve significant symptom control and improved long-term outcomes.

Interprofessional Team Approach to Diagnosis and Management of Behcet’s Disease

Effective diagnosis and management of Behcet’s disease require a collaborative, interprofessional healthcare team. Given the multisystem nature of BD, specialists from various disciplines are often involved. The team may include:

• Rheumatologist: Central role in coordinating care, managing systemic inflammation, and immunosuppressive therapy.
• Ophthalmologist: Essential for diagnosis and management of ocular manifestations, preventing vision loss.
• Dermatologist: For diagnosis and management of mucocutaneous lesions and pathergy testing.
• Neurologist: For diagnosis and management of neuro-Behcet’s disease.
• Gastroenterologist: For diagnosis and management of intestinal Behcet’s disease.
• Vascular Surgeon/Cardiologist: For managing vascular complications, such as aneurysms and thrombosis.
• Internist/Primary Care Physician: For overall medical management and coordination of care.
• Pharmacist: To ensure medication adherence, monitor for drug interactions and side effects, and provide patient education on medications.
• Nurses: To provide patient education, monitor symptoms, assist with wound care, and coordinate communication among team members.
• Wound Care Specialists: For management of complex skin ulcers.

Enhancing Healthcare Team Outcomes:

• Early Diagnosis and Recognition: Prompt recognition of BD and its organ involvement is critical to initiate timely treatment and prevent organ damage.
• Interdisciplinary Communication: Regular communication and information sharing among team members are essential for coordinated care planning.
• Patient Education: Comprehensive patient education about the disease, treatment options, potential complications, and the importance of medication adherence is crucial for patient empowerment and improved outcomes.
• Personalized Treatment Plans: Treatment strategies should be tailored to the individual patient’s disease manifestations, severity, and preferences.
• Long-term Monitoring: Regular follow-up and monitoring for disease activity, treatment response, and potential complications are essential for optimal long-term management.

By fostering a collaborative and well-coordinated interprofessional team approach, healthcare providers can optimize the diagnosis of Behcet’s disease, improve patient care, and enhance outcomes for individuals living with this complex condition.

Review Questions

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References

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Disclosures: (Disclosures are kept the same as the original article)

Disclosure: Abdullah Adil declares no relevant financial relationships with ineligible companies.

Disclosure: Amandeep Goyal declares no relevant financial relationships with ineligible companies.

Disclosure: Jessilin Quint declares no relevant financial relationships with ineligible companies.