Behçet’s Disease in Children: Diagnostic and Management Challenges

Figures & data

Table 1 Clinical Manifestations in Pediatric and Adult BD Cohorts

			Pediatric Series						Adult Series
Reference	Koné-Paut^Citation51	Shahram^Citation52	Atmaca^Citation53	Karingcaoglu^Citation15	Gallizzi^Citation16	Koné-Paut^Citation21	Makmur^Citation54	Krause^Citation55	Alpsoy^Citation1,Citation15	Makmur^Citation54	Krause^Citation55
Number of patients	156	204	110	83	110	65	46	19	661	560	34
Oral aphtosis (%)	100	91.7	100	86	94.5	96	97.8	100	100	96.6	100
Genital ulcers (%)	55.1	42.2	82.7	81.9	33.6	70	73.9	31.6	58.3	75.7	88.2
Skin lesions (%)	66.6	51.5	37.3	51.8	39.6	76	21.7	89.5	44.2 (Erythema nodosum) 55.4% (pseudo folliculitis)	55.4	82.4
Pathergy positivity (%)	N/A	57	45.5	37.3	14.5	NA	NA	41.2	37.8	NA	57.1
Ocular involvement (%)	45.5	66.2	61.8	34.7	43.6	60	4.3	47.4 (anterior uveitis) 42.1 (posterior uveitis) 10.5 (retinal vasculitis)	29.2	37	Approx. 50%
Arthralgia/arthritis (%)	41	30.9	22.7	39.8	42.7	56	21.7 (arthritis)	47.4**	33.4	9.6**	17.6
Gastrointestinal involvement (%)	29.4	5.9	NA	4.8	42.7	14	21.7	36.8	1.6	4.5	11.7
Neurological involvement (%)	5*	4.4*	3.6*	7.2*	NA	15	NA	26.3	3*	NA	5.8*
Vascular involvement (%)	14.7	6.4	3.6	7.2	1.8	15	6.5	10.5	4.4	17.5	26.5

Notes: *Other than headaches. **Patients with only arthralgia are not included.

Abbreviation: NA, not available.

Table 2 Differential Diagnosis of Patients with BD According to Clinical Manifestations

Recurrent Oral Ulcerations

Ocular Involvement

Idiopathic aphtosis Infections (HSV, HIV) Nutritional deficiencies (Vitamins B1, B2, B6, B12 Folate, Iron, Zinc) Cyclic neutropenia Erythema multiforme Inflammatory bowel disease (Ulcerative colitis Chron’s diseases) Celiac disease Systemic lupus erythematosus Reactive arthritis Autoinflammatory diseases (PFAPA, Familial Mediterranean fever, Hyperimmunoglobulinemia D) Genital ulcerations Infections (HSV, HIV, syphilis) Erythema multiforme Gastrointestinal involvement Inflammatory bowel disease (Ulcerative colitis Chron’s diseases) Neurological involvement Multiple sclerosis CNS vasculitis Stroke Idiopathic and secondary intracranial

Juvenile idiopathic arthritis (JIA) Reactive arthritis Vogt-Koyanagi-Harada syndrome, Idiopathic intermediate uveitis (pars planitis) Tubulointerstitial nephritis and uveitis syndrome Crohn’s disease Cogan Syndrome Sarcoidosis Vascular involvement Antiphospholipid syndrome Thrombophilia Takayatsu’s arteritis hypertension (CNS lymphomas, intracranial neoplasia) CNS sarcoidosis CNS tuberculosis Other causes of CVS thrombosis (e.g. mastoiditis)

Abbreviations: HSV, herpes simplex virus; HIV, human immunodeficiency virus; PFAPA, periodic fever aphtas pharyngitis and cervical adenopathies; CNS, central nervous system; CVS, cerebral venous sinus.

Table 3 Consensus Classification of Pediatric Behçet Disease

Item	Description	Value/Item
Recurrent oral aphtosis	At least three attacks/year	1
Genital ulceration and aphtosis	Typically with scar	1
Skin involvement	Necrotic folliculitis, acneiform lesions, erythema nodosum	1
Ocular involvement	Anterior uveitis, posterior uveitis, retinal vasculitis	1
Neurological signs	With the exception of isolated headaches	1
Vascular signs	Venous thrombosis, arterial thrombosis, arterial aneurysm	1

Note: Three of six items are required to classify a patient as having pediatric Behçet disease. Data from Kone-Paut et al.⁴⁹

Table 4 Recommended Therapies for the Major Clinical Manifestations of BD

Clinical Manifestations	First Line	Second Line	Other Options
Mucocutaneous involvement	Topical corticosteroids Colchicine (prevention)	AZA IFNα Etanercept Infliximab Adalimumab	Apremilast* MTX Anakinra Canakinumab Ustekinumab Secukinumab Thalidomide
Arthritis	Intra-articular steroids Colchicine	Low-dose steroids AZA IFNα Infliximab Adalimumab	Secukinumab
Eye involvement	Corticosteroids** AZA Cyclosporine (Infliximab)# (Adalimumab)#	Infliximab Adalimumab IFNα	Intravitreal steroids*** MTX Anakinra Canakinumab Tocilizumab Rituximab
Neuro-Behçet	Corticosteroids AZA Anticoagulation**** (Infliximab)# (Adalimumab)#	Infliximab Adalimumab	MMF MTX Tocilizumab Rituximab
Arterial involvement	Corticosteroids Cyclophosphamide*****	Infliximab Adalimumab	Surgery/Stenting
GI involvement	Corticosteroids 5-ASA AZA	Infliximab Adalimumab	Thalidomide

Notes: *Recurrent oral ulcers; **posterior uveitis; ***acute exacerbation in one eye, ****deep Venous Thrombosis; *****arterial aneurysms; #first-line treatment in severe cases.

Abbreviations: 5-ASA, 5-aminosalicylate; AZA, azathioprine; IFNα, interferon-α; GI, gastrointestinal; MMF, mycophenolate mofetil; MTX, methotrexate.

Table 5 Molecular Targets and Treatment Options

Target	Clinical Significance	Drugs
TNF-α	Pro-inflammatory cytokine, mainly produced by monocytes.	Infliximab (chimeric anti-TNF-α antibody) Adalimumab (human anti-TNF-α antibody) Etanercept (soluble TNF-α receptor) Golimumab (human anti-TNF-α antibody)
IL-1	Pro-inflammatory cytokine, mainly produced by monocytes and dendritic cells.	Anakinra (IL-1 receptor antagonist) Canakinumab (human anti-IL-1antibody) Gevokizumab (humanized anti-IL-1 antibody)
IL-6	Pro-inflammatory cytokine, produced by macrophages and T cells.	Tocilizumab (humanized anti-IL-6antibody)
IL-17	Cytokine produced by Th-17 cells. Uveitogenic activity.	Secukinumab (human anti-IL-17A antibody)
IL-23	Cytokine with inflammatory properties, including the induction of Th-17 response.	Ustekinumab (human anti-IL-12/IL-23 antibody)
CD20	Expressed by B-lymphocytes. Targeted in B-mediated diseases, including lymphomas and autoantibody-mediated pathologies.	Rituximab (chimeric anti-CD20 antibody)
CD25	Component of the IL-2 receptor. Its activation promotes the differentiation and proliferation of T cells.	Daclizumab (humanized anti-CD25 antibody)
CD52	Expressed by mature lymphocytes. Targeting CD52 causes lymphocyte depletion.	Alemtuzumab (humanized anti-CD52 antibody)

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