What are the differential diagnoses for a patient in their 30s with a history of Deep Vein Thrombosis (DVT), pulmonary embolism, HLA B51 positivity, and recurrent cutaneous vasculitis, without oral and genital aphthae?

Differential Diagnoses for a Patient in Their 30s with DVT, PE, HLA-B51 Positivity, and Recurrent Cutaneous Vasculitis Without Oral/Genital Aphthae

Behçet's disease remains the primary differential diagnosis despite the absence of oral and genital aphthae, given the constellation of HLA-B51 positivity, recurrent cutaneous vasculitis, and venous thromboembolism—particularly because mucocutaneous lesions may develop later in the disease course or may be subtle and overlooked. 1, 2

Primary Differential: Behçet's Disease (Incomplete Presentation)

Behçet's disease should be strongly considered even without the classic mucocutaneous findings, as the disease follows a relapsing-remitting course where different manifestations can appear over years 2, 3. The combination of findings in this patient is highly suggestive:

• HLA-B51 positivity has a negative predictive value of 84-90%, meaning its presence significantly increases suspicion for Behçet's disease, though the positive predictive value is only 55% 4
• Vascular involvement occurs in Behçet's disease and includes both arterial and venous thrombosis, with venous lesions causing occlusion as seen with DVT and PE 5, 6
• Cutaneous vasculitis is a recognized manifestation that can present as palpable purpura, infiltrated erythema, or nodular lesions 7, 3
• Oral and genital aphthae may not yet have appeared, as Behçet's disease manifestations develop gradually over years, and the disease may start with just one or two symptoms 2, 3

Key Clinical Pitfall

The absence of oral and genital ulcers should not exclude Behçet's disease from consideration, as these may develop later or may have been subtle and unrecognized 8, 2. Specifically question the patient about any history of recurrent mouth sores or genital lesions that may have been dismissed as minor 3.

Other Critical Differentials to Exclude

Antiphospholipid Antibody Syndrome (APS)

• Must be excluded given the thrombotic presentation with DVT and PE in a young patient 8, 7
• Test for lupus anticoagulant, anticardiolipin antibodies, and anti-β2-glycoprotein-1 antibodies 8
• APS can present with cutaneous manifestations including livedo reticularis and thrombotic vasculopathy 7

ANCA-Associated Vasculitis

• Consider microscopic polyangiitis or Wegener granulomatosis given the cutaneous vasculitis 7
• These conditions can present with small-vessel vasculitis and systemic involvement 7
• Check ANCA (c-ANCA and p-ANCA) levels 8
• However, venous thromboembolism is less characteristic than in Behçet's disease 7

Inherited Thrombophilias

• Factor V Leiden and prothrombin G20210A mutations should be tested given the unprovoked VTE in a young patient 8
• Also evaluate for deficiencies in antithrombin, Protein C, and Protein S 8
• These would not explain the cutaneous vasculitis or HLA-B51 positivity but may be contributing factors 8

Connective Tissue Diseases

• Systemic lupus erythematosus (SLE) can present with cutaneous vasculitis and thrombosis (especially if APS is present) 7
• Check ANA, anti-dsDNA, complement levels (C3, C4) 7
• Rheumatoid vasculitis is less likely given the age and presentation but should be considered 7

Malignancy-Associated Vasculitis

• Occult malignancy can present with cutaneous vasculitis and hypercoagulability (Trousseau syndrome) 8, 7
• Age-appropriate cancer screening should be performed 7
• Coexistence of pan-dermal small-vessel vasculitis and subcutaneous muscular-vessel vasculitis may indicate malignancy-associated vasculitis 7

Recommended Diagnostic Workup

Immediate Laboratory Evaluation

• Thrombophilia panel: Factor V Leiden, prothrombin G20210A, antithrombin, Protein C, Protein S, Factor VIII levels 8
• Antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein-1 antibodies 8
• ANCA testing (c-ANCA and p-ANCA) 8, 7
• Autoimmune serologies: ANA, anti-dsDNA, complement levels (C3, C4), rheumatoid factor 7
• Inflammatory markers: ESR, CRP 7

Skin Biopsy

• Obtain a deep biopsy extending to the subcutis from the most tender, reddish, or purpuric lesional skin 7
• Request serial sections to identify the main vasculitic lesion 7
• Include direct immunofluorescence to distinguish IgA-associated vasculitis (Henoch-Schönlein purpura) from IgG-/IgM-associated vasculitis 7
• Coexistence of pan-dermal small-vessel vasculitis and subcutaneous muscular-vessel vasculitis suggests Behçet's disease, connective tissue disease, ANCA-associated vasculitis, or malignancy-associated vasculitis 7

Additional Investigations

• Pathergy test (if available) to support Behçet's disease diagnosis 3, 9
• Ophthalmologic examination to evaluate for subclinical uveitis, as ocular involvement occurs in approximately 50% of Behçet's cases 3, 9
• Age-appropriate malignancy screening given the association between vasculitis and occult malignancy 7

Management Considerations Pending Diagnosis

• Continue anticoagulation for the acute DVT/PE as per standard guidelines 8
• If Behçet's disease is confirmed, the European League Against Rheumatism recommends mandatory treatment with glucocorticoids and immunosuppressives for acute deep vein thrombosis, with monoclonal anti-TNF antibodies for refractory venous thrombosis 1
• Avoid leg elevation alone; this patient requires systemic therapy given the severity of presentation 7
• Do not delay immunosuppression if major organ involvement from Behçet's disease is confirmed, as this can result in permanent damage 1

Critical Pitfall to Avoid

Anticoagulation of pulmonary artery aneurysms is not recommended if Behçet's disease is confirmed and arterial involvement develops, due to bleeding risk 1. Ensure imaging distinguishes between thrombotic PE and potential aneurysmal disease 5, 6.