What are the differential diagnoses for a patient with suspected Behcet's disease?

Differential Diagnoses for Behçet's Disease

When evaluating a patient with suspected Behçet's disease, the differential diagnosis must systematically exclude inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis (for neurological presentations), infectious causes (particularly tuberculosis and syphilis), other vasculitides, and hematologic malignancies. 1

Mucocutaneous Manifestations - Key Differentials

Oral and Genital Ulcerations

• Inflammatory bowel disease (Crohn's disease and ulcerative colitis) must be excluded through endoscopy and imaging, as gastrointestinal ulcerations can mimic Behçet's disease 1
• Systemic lupus erythematosus presents with oral ulcers but typically has positive ANA, anti-dsDNA antibodies, and different systemic features 2
• Herpes simplex virus and other viral infections should be ruled out, particularly for genital ulcerations 3
• Aphthous stomatitis (isolated) lacks the systemic features and recurrent genital involvement seen in Behçet's disease 4

Skin Lesions

• Erythema nodosum from other causes (sarcoidosis, tuberculosis, streptococcal infection) must be differentiated, though erythema nodosum-like lesions carry more diagnostic weight for Behçet's disease than acneiform lesions 1
• Sweet syndrome can present with papulopustular lesions and systemic inflammation 3
• Pyoderma gangrenosum associated with inflammatory bowel disease shares similar ulcerative skin manifestations 3

Ocular Involvement - Critical Differentials

• Sarcoidosis causes uveitis and should be excluded with chest imaging, ACE levels, and biopsy when indicated 3
• Multiple sclerosis can present with optic neuritis and requires MRI with contrast to differentiate from neuro-Behçet's 1
• Infectious uveitis (tuberculosis, syphilis, toxoplasmosis, herpes viruses) must be ruled out with appropriate serologic and microbiologic testing 3
• Other autoimmune uveitis including HLA-B27-associated conditions and Vogt-Koyanagi-Harada disease 5

Neurological Involvement - Essential Exclusions

For patients presenting with neurological symptoms, MRI with contrast is the imaging modality of choice, and CSF analysis may show pleocytosis and elevated protein levels. 1

• Multiple sclerosis is a critical differential for neuro-Behçet's and requires careful evaluation of MRI patterns, CSF oligoclonal bands, and clinical course 1
• Neurosarcoidosis presents with similar CNS manifestations and requires exclusion 1
• Primary CNS vasculitis (isolated angiitis of the CNS) affects predominantly young women, shows normal ESR, negative serologic studies, and characteristic angiographic findings of multifocal segmental narrowing 4
• CNS infections including neurosyphilis, neurotuberculosis, and viral encephalitis must be excluded 3

Vascular Involvement - Key Considerations

Vascular involvement occurs in approximately one-third of Behçet's patients, affecting both arteries and veins, making it one of only two vasculitides with significant venous involvement. 6, 7

• Deep vein thrombosis from other causes (hypercoagulable states, malignancy, antiphospholipid syndrome) requires appropriate thrombophilia workup 6
• Other large vessel vasculitides (Takayasu arteritis, giant cell arteritis) typically lack the mucocutaneous features of Behçet's disease 8
• Infectious aortitis particularly syphilitic aortitis, should be excluded with appropriate serologic testing 2
• Hughes-Stovin syndrome (pulmonary artery aneurysms with thrombophlebitis) may represent a variant of Behçet's disease 5

Gastrointestinal Involvement - Important Differentials

Gastrointestinal involvement requires confirmation through endoscopy and/or imaging, with careful exclusion of NSAID-induced ulcers, inflammatory bowel disease, and infections like tuberculosis. 1

• Crohn's disease is the most important differential, as both affect the ileocecal region with ulcerations that may perforate 9
• Intestinal tuberculosis must be excluded, particularly in endemic areas, through appropriate microbiologic and histopathologic evaluation 1, 9
• NSAID-induced ulcers should be considered in the medication history 1
• Intestinal lymphoma and other malignancies can present with similar ulcerative lesions 9

Systemic Inflammatory Conditions

• Adult-onset Still's disease presents with fever, rash, and arthritis but has characteristic salmon-pink rash, extremely elevated ferritin (often >5000 ng/mL), and lacks the mucocutaneous ulcerations of Behçet's disease 2
• Reactive arthritis can present with oral ulcers, genital lesions, and arthritis but typically follows genitourinary or gastrointestinal infection 3
• Relapsing polychondritis shares some features but has characteristic auricular and nasal cartilage involvement 2

Infectious Causes Requiring Exclusion

• Syphilis can cause oral and genital ulcers, uveitis, and vasculitis; serologic testing (RPR, VDRL, treponemal-specific tests) is essential 2, 4
• Tuberculosis must be excluded, particularly before initiating immunosuppressive therapy, through tuberculin skin testing or interferon-gamma release assays 7, 9
• HIV infection can present with oral ulcers and various systemic manifestations 3
• Herpes viruses (HSV, VZV, EBV, CMV) should be considered, particularly for mucocutaneous lesions 3

Hematologic and Neoplastic Conditions

• Hemophagocytic lymphohistiocytosis (HLH) can present with fever and systemic inflammation but has characteristic cytopenias, extremely elevated ferritin (often >10,000 ng/mL), and elevated IL-18 levels that distinguish it from Behçet's disease 2
• Leukemia and lymphoma can present with oral ulcers and systemic symptoms 2

Diagnostic Approach to Differentiation

HLA-B51 testing has moderate positive predictive value (approximately 55%) and high negative predictive value (84-90%) but should not be used as a standalone diagnostic test. 1

• Inflammatory markers (ESR, CRP) are elevated in Behçet's disease but are nonspecific and can be elevated in all the differential diagnoses listed 1, 6
• Complete blood count should be performed to assess for cytopenias (suggesting HLH or malignancy) versus leukocytosis or thrombocytosis (seen in active Behçet's disease) 1
• Pathergy testing is specific for Behçet's disease but has variable sensitivity depending on geographic region 1, 5

Common Pitfalls in Differential Diagnosis

• Failing to perform thorough genital examination may miss genital ulcers or scars, which are critical diagnostic features 1, 6
• Incomplete ophthalmologic evaluation may miss posterior uveitis or retinal vasculitis, which are both diagnostic criteria and poor prognostic factors 1, 6
• Assuming isolated oral ulcers are Behçet's disease without waiting for additional manifestations or excluding other causes 3
• Missing concurrent inflammatory conditions such as spondylodiscitis, which can present with vertebral erosion and may coexist with or mimic Behçet's disease 2