Pediatric Behçet Disease

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1 Review Article Pediatric Behçet Disease Mustafa Çakan, Nuray Aktay Ayaz Istanbul Kanuni Sultan Süleyman Research and Training Hospital, Clinic of Pediatric Rheumatology, Istanbul, Turkey Corresponding Author: Dr. Mustafa Çakan Kanuni Sultan Süleyman Eğitim ve Araştırma Hastanesi Çocuk Romatoloji Polikliniği Halkalı, Küçükçekmece, İstanbul, Türkiye Received: Jun 20, 2017 Accepted: Sep 25, 2017 Ann Paediatr Rheum 2017;6:67-77 DOI: /apr Abstract Behçet disease is an inflammatory disorder characterized by recurrent oral and genital ulcerations, uveitis, cutaneous, musculoskeletal, vascular, gastrointestinal and neurological manifestations. It is also classified as variable vessel vasculitis because it can affect any size and type of vessel in any part of the body. Mucocutaneous manifestations are the initial symptoms and signs in the majority of the cases but ocular, vascular and neurological manifestations are the leading causes of morbidity and mortality. The disease is rare in childhood and most commonly affects men between the ages of years and follows a more severe course in males. The pathogenesis of the disease still remains obscure. The prevalence of Behçet disease is much more common in the zone of old Silk Road that extends from countries of Middle East and Mediterranean basin to Far East Asia. There is no any pathognomonic clinical, laboratory, imaging or histopathological abnormality and diagnosis is based on the constellation of the clinical findings. Recurrent oral aphthosis is the most common initial finding but most children develop other diagnostic signs and symptoms of the disease many years later. There is no cure for Behçet disease and treatment is aimed at alleviating inflammation and vasculitis that is directed by major organ involvement. Colchicine is the mainstay of the therapy and immunosuppressive drugs like azathioprine, cyclosporine A, cyclophosphamide are used depending on the type and severity of the organ involved. Biological drugs, especially TNF-α inhibitors and interleukin-1 antagonists, seem to be showing promising results in resistant cases. Key words: Behçet disease, child, clinical features, diagnosis, treatment Introduction Behçet disease (BD) is an inflammatory disorder characterized by recurrent oral and genital aphthous ulcers, uveitis and skin lesions [1]. It was described by a Turkish dermatologist, Dr. Hulusi Behçet in 1937 [2]. In 2012, BD was classified as variable vessel vasculitis because it can affect vessels of any size and type [3]. It is also considered as an autoinflammatory disorder because of the recurrent and mostly self-limited attacks of the disease

2 Pediatric Behçet Disease 68 [1]. The typical findings of the disease are due to mucocutaneous, eye and skin involvement. Vascular, gastrointestinal and nervous system involvement may lead to mortality [1]. Epidemiology The prevalence of the disease shows dramatic differences in between countries. It is most commonly observed in the countries of old Silk Road namely, Far East Asia, Middle East and Mediterranean basin [4]. Turkey and Japan have the highest prevalence of the disease and the prevalence of the disease in Turkey is around 1/250. It most commonly affects males between the ages of years [1,5]. Behçet disease is rarely encountered in pediatric age group [1,6]. The first BD symptoms may start early in life but the disease is rarely completed before the age of 16 years in 4%- 26% of cases [7,8]. It is estimated that the prevalence of pediatric BD is 10/ in Turkey, and 1/ in France [1]. There is a male dominance in adults (male/female; 2-3/1) but it equally affects both genders in children [6,7]. The mean age at diagnosis is around 13 years in pediatric age group [8]. Etiopathogenesis The etiology of BD still remains undefined. It is believed that in a genetically susceptible host, the trigger of an unknown environmental factor causes increased immune response resulting in damage and clinical findings. The constellation of the cases in defined geographical locations, the presence of familial cases and observation of genetic anticipation in familial cases suggest that genetic contribution in disease evolution is high [1,9,10,11]. Around 10.8%-12.3% of all BD patients are familial cases. The disease is manifested much earlier and more severe in the next generation [11-13]. The most important and consistent genetic risk factor described is HLA-B51 positivity. Overall, HLA-B51 positivity is seen in 40%-80% of BD patients [14]. In Turkish population, the positivity of HLA-B51 is 75% but it is also positive in 24.7% of healthy population [15]. The negativity of HLA-B51 in 20%- 60% of the BD patients and high rate of HLA-B51 positivity with low prevalence of BD (2/ ) in some countries like Italy and Portugal, led to consider that other genetic determinants may be important in disease pathogenesis. Genomewide association studies (GWAS) that were done in patients from different ethnic backgrounds revealed that having single nucleotide polymorphisms (SNPs) in HLA-A26, UBAC2, IL10, IL23R-IL12RB2, STAT4, ERAP1, GIMAP, KLRK1- KLRKC1 and CCR1-CCR3 genes increases the risk of BD [9,16,17]. Recent definition of haploinsufficiency of A20, that leads to increased expression of NFκB-mediated proinflammatory cytokines, as a monogenic cause of BD shed an important and breakthrough development in understanding the pathophysiology of BD, highlighting the importance of the ubiquitination pathway [18]. The most important environmental triggering factor considered in the etiopathogenesis of BD is Streptoccus sanguinis. S.sanguinis, especially KTH1 serotype, is found more commonly in the oral flora of BD patients. It was shown that the stimulation T cells and mononuclear cells of BD patients by KTH1 antigen causes over production of IFN-gamma and IL-12 [19]. The studies are more focused on the over activity of IL-23/IL-17 axis and inflammation caused by Th1 and Th17 cells. IL-12 causes naïve T cells mature in the direction of Th1 cells and IL-23 is necessary for Th17 maturation. SNPs that were found by GWAS in the IL23R-IL12RB2 genes and in STAT4 gene, that is a transcription factor necessary for IL- 12 and IL-23 production, support this opinion. One of the hypotheses in the pathogenesis of BD is misfolding hypothesis. ERAP1 is an aminopeptidase that is expressed in the endoplasmic reticulum. The function of ERAP1 is processing and loading the peptides that are derived from microbial agents onto MHC Class I molecules. HLA Class I molecule needs to be folded when a peptide attaches to it. If misfolding occurs, it creates stress in endoplasmic reticulum that leads to activation of IL-23/IL-17 pathway and inflammation [1,16,17,20,21]. SNPs found in ERAP1 gene seem to be supporting this hypothesis. Misfolding hypothesis is also valid for other HLA Class I associated diseases like ankylosing spondylitis (HLA- B27) and psoriasis (HLA-C06) [22]. Clinical Manifestations Behçet disease follows a course with spontaneous exacerbations and remissions. Most of the patients do not demonstrate all clinical features at the beginning of the disease and new symptoms are added onto each other by time. Since BD is a clinical diagnosis, all suspected cases should be followed carefully for the occurrence of new symptoms and signs [23]. DOI: /apr

3 69 Cakan M et al. Figure 1. The view of the clinical features in Behçet disease a) minor aphthous ulcers on the lip and tongue b) major aphthous ulcers on the lip and tongue c) healing genital ulcer on the scrotum d) pseudofolliculitis on the left upper leg in a prepubertal boy e) stasis dermatitis on the right lower leg secondary to chronic superficial thrombophlebitis f ) swelling of the whole right leg secondary to chronic deep vein thrombosis. Mucocutaneous, eye and musculoskeletal manifestations are common in all races but vascular involvement is more common in Mediterranean and Middle Eastern countries, whereas gastrointestinal (GI) involvement is much more common in Far East Asian countries [24]. Mucocutaneous, eye, and musculoskeletal signs and symptoms are observed at the initial stages of the disease but GI, central nervous system (CNS) and major vessel involvement is generally seen during the following months or years [23]. The symptoms and signs tend to be in clusters like acne/arthritis/enthesitis cluster and vascular cluster (involvement of dural sinuses, superficial and deep veins and pulmonary arteries) [9,24]. Females tend to have higher incidence of genital ulcers and erythema nodosum while male gender is associated with severe uveitis, vascular disease and higher mortality [10]. Mucocutaneous Manifestations Recurrent oral aphthous ulcers are the initial manifestations of BD in children as in adults. They tend to be multiple and painful. They may be minor (< 10 mm in diameter), major (> 10 mm in diameter), herpetiform or necrotic. Around 90% of them are minor lesions and may be located in the oral mucosa, tongue, lips or anywhere in the GI tract (Figure 1a, b). Minor lesions heal in 7-10 days but major lesions heal in weeks and recur every one or two months [1,6,7,10]. Recurrent oral ulcers start to be seen around 7 years of age and oral ulcers may be the only manifestation of the for 6-7 years before the second major manifestation is evident [6,7,8,10]. But, it should be remembered that nearly 20% of healthy population has recurrent oral aphthae which may be idiopathic or secondary to trauma, viral or bacterial infections [25]. The clinical features of oral ulcers secondary to BD and isolated recurrent oral aphthae are indistinguishable, so patients with the complaint of recurrent oral aphthae should be followed carefully for the development of other signs and symptoms of BD [23]. The most important warning sign for BD is the development of recurrent genital ulcers. It tends to be located in the Annals of Paediatric Rheumatology Year 2017 Volume:6 Issue:

4 Pediatric Behçet Disease 70 penis, scrotum and perianal region in boys and vulva and vagina in girls (Figure 1c). They may heal with scarring and deeper ulcers have higher probability of scarring [1,6,7]. One Turkish study found that in 83 pediatric BD patients, the frequency of oral and genital ulcers were 100% and 81.9%, respectively [6]. Another international registry system that included 110 pediatric BD patients found that the frequency of oral ulcers was 100% and that was 61% for genital ulcers [12]. Erythema nodosum, acneiform nodules, folliculitis, pseudofolliculitis, papulopustular or ulcerative skin lesions are other skin lesions that can be seen around 90% of the patients (Figure 1d) [1,6,12]. Pathergy test, which demonstrates non-specific hyperreactivity of the skin to trauma, is used for many years as a supportive test in the diagnosis of BD. Pathergy test is applied to volar aspects of the forearms by oblique insertion of 20G needle into the skin. Three insertions are made onto both arms and the test is considered as positive if at least one of the six pricks form pustule that is wider than 2 mm in hours. Pathergy test is positive in 40%-70% of pediatric BD patients like in adults. The possibility of positivity is high in Middle Eastern and Japanese patients but low in European and North American patients [5,6,12,26]. It is highly specific but not pathognomonic for BD and may be observed also in pyoderma gangrenosum, Sweet syndrome, inflammatory bowel disease, and acute myeloid leukemia treated with interferon alpha [27-29]. Eye manifestations Eye involvement in the BD is one of the most severe manifestations of the disease and has high rate of morbidity including blindness. The frequency of eye involvement in pediatric BD is around 30%-61% similar to that of adult ratio [1,6,14]. Eye involvement is most commonly seen in young men at the early stages of the disease and ocular manifestations tend to be more severe, recurrent and resistant to treatment in males [14,30]. Eye involvement may be the first manifestation of BD in 20% of the patients even before the occurrence of oral aphthae [31]. Involvement may be in the form of anterior uveitis (iridocyclitis with hypopyon), posterior uveitis or panuveitis. The hypopyon that is found in the anterior chamber contains minimal fibrinous exudate and it is not attached tightly to the surrounding tissues, so it moves concomitantly with the movements of the head. The involvement of the eye is bilateral in 80% of the patients [14,31,32]. Bilateral posterior uveitis with retinal vasculitis is the most typical feature of ocular BD [10]. BD should be in the differential diagnosis list of all patients with unexplained retinal vasculitis [9]. Fluorescein angiography is the gold standard method in the evaluation of leaky and occlusive retinal vasculitis. Laser flare photometry is a noninvasive, objective and quantitative way of measuring flare (protein content) in the aqueous humor. Optical coherence tomography reveals retinal and choroidal thickness changes and may be helpful for the detection of macular hole, cystoid macular edema, and retinal atrophy [30]. Corneal ulcerations, retinal detachment, retrobulbar neuritis are rare manifestations of the eye involvement. Cataract, posterior synechiae, and cystoid macular edema are the most common complications. Ocular involvement tend to have multiple attacks and in untreated cases may lead to blindness [1,31,32]. Neurological Manifestations Neurological involvement is seen in 5%-15% of the patients. CNS involvement is much more common than peripheral nervous system involvement that is reflected as mononeuropathy [1,29]. CNS involvement is divided into two major groups; one is due to parenchymal involvement, that is an inflammatory meningo-encephalitic process, and the other one is non-parenchymal involvement secondary to vascular involvement of CNS circulatory system [29]. In adult neuro- Behçet disease (NBD), parenchymal involvement manifested as meningoencephalitis is most commonly seen and nonparenchymal cerebral sinus venous thrombosis is the most common form of pediatric NBD [1,6,12,29]. One study including 702 adult NBD and 26 pediatric NBD cases revealed that 88.5% of pediatric NBD was secondary to dural venous sinus thrombosis only 3 pediatric NBD cases were due to parenchymal involvement. It is recommended that every patient with cerebral venous thrombosis should be searched for BD [9,33]. The same study showed that mean age at diagnosis of pediatric BD was 13.0 ± 3.0, and mean age at the diagnosis of pediatric NBD was 13.5 ± 2.4 [33]. Clinical features in parenchymal involvement may be DOI: /apr

5 71 Cakan M et al. acute or chronic progressive and develop secondary to the involvement of the cerebrum, brain stem, spinal cord and optic nerve. Acute manifestations are headache, aseptic meningitis, ophthalmoparesis, cranial nerve palsies, encephalopathy, convulsion and hemiparesis. Chronic progressive lesions lead to cognitive dysfunction, memory loss, depression, anxiety and psychosis. Cerebral sinus venous thrombosis leads to increased intracranial pressure (pseudotumor cerebri) that is clinically reflected as headache and vomiting [9,10,29,33,34]. Multiple high intensity focal lesions in the brain stem, basal ganglia, and cerebral white matter are typical findings on T2- weighted magnetic resonance imaging (MRI). One of the main diagnostic challenges in NBD is multiple sclerosis. The presence of subcortical lesions and brainstem atrophy in MRI is considered as highly specific for NBD especially if other clinical manifestations of BD are present [29]. Non-parenchymal involvement is usually monophasic but parenchymal involvement is usually progressive with exacerbations and remissions [29]. Vascular Manifestations Vascular involvement of BD is different from other primary and secondary vasculitides as it may affect vessel of any size and type. Thrombosis in the veins and arteries, aneurysms or occlusions in the arteries are all possible consequences of vascular involvement [3]. Vascular involvement may be classified as systemic arterial vasculitis, pulmonary arterial involvement, venous occlusions and varices [35]. Vascular involvement is seen in 3%-7.6% of the patients [6,7,12,35]. Venous involvement as superficial or deep venous thrombosis in the lower extremities is the most common form of vascular involvement. The lesions cause local pain, swelling, stasis dermatitis and skin ulcers (Figure 1e, f ). Arteritis or aneurysms in the aorta and its main branches may be observed [1,35]. Pulmonary artery aneurysm or thrombosis is rare but morbidity and mortality is high due to the risk of hemoptysis and massive pulmonary hemorrhage. The main pathologic event in BD vasculitis is the inflammation of the vessel wall that may end with thrombus formation, aneurysm or occlusion of the lumen. Thrombosis in BD is very adherent to vascular wall and the risk of secondary embolization is very low so, anticoagulation treatment in BD thrombosis is a debated topic. Especially, in patients with pulmonary artery involvement, anticoagulation may lead to fatal bleedings [9,10,35]. The presence of superficial thrombophlebitis is accepted as a warning sign for major vessel involvement, so patients with superficial thrombosis should be looked for signs and symptoms of vena cava thrombosis, Budd-Chiari syndrome, pulmonary artery aneurysm/thrombosis, and aorta involvement. It is recommended that patients with thrombosis should also be searched for other primary and secondary causes of thrombosis [1,35]. Musculoskeletal Manifestations Nearly half of the patients have arthralgia/arthritis [1,6,12]. Polyarticular involvement is possible but oligoarticular involvement is much more common. Knee, ankle, wrist, and elbow are the most commonly involved joints. Erosions or deformities are not expected to be seen [1]. Muscle involvement in the form of myositis is reported in a few cases and is not an expected usual manifestation of the disease [36,37]. Gastrointestinal System Manifestations Gastrointestinal involvement is more commonly seen in pediatric patients than adults [38]. GI involvement also differs with geographical location and most commonly seen in Far East Asian patients [38]. In Turkey, 1.3% of adult cases and 4.8% of pediatric cases have GI involvement [6]. Any part of the GI tract may be involved. Ileocecal region and colon is the most commonly involved parts while stomach is the least commonly involved part of the GI tract [38]. Patients may complain of abdominal pain, diarrhea, and hematochezia. Endoscopic examination reveals isolated or multiple deep ulcers that closely resembles that of inflammatory bowel disease (IBD). The ulcers of BD tend to be circular or oval, punchedout lesions while ulcers of Chron s disease tend to be more longitudinal [1,38]. Other Manifestations Renal involvement in BD may be in the form of amyloidosis, glomerulonephritis, interstitial nephritis, renal artery aneurysms, or renal vein thrombosis. Renal involvement in pediatric BD is rarely seen [1,39]. Cardiac involvement is seen in 1%-6% of adult cases but also rarely seen in pediatric BD. Patients with any form of vascular involvement have high risk of cardiac involvement [35]. Pericarditis, myocarditis leading Annals of Paediatric Rheumatology Year 2017 Volume:6 Issue:

6 Pediatric Behçet Disease 72 to conduction deficits, endocarditis leading to valvular insufficiencies, intracardiac thrombosis, endomyocardial fibrosis, and coronary arteritis are possible manifestations of cardiac involvement. Pericarditis is the most common form of cardiac involvement and tends to show frequent recurrences that heal rapidly without sequela. Rarely, intracardiac thrombosis located in the right atrium or ventricle may be the first manifestation of the disease. This picture is more commonly seen in Mediterranean and Middle Eastern young men and reflected as fever, cough and dyspnea [35]. In some children, recurrent fever attacks may be the only manifestation mimicking periodic fever syndromes. Fever in a BD patient is regarded as an important warning sign for vascular or neurologic involvement [10,37]. Laboratory There is no any laboratory test, histopathologic or imaging finding that is diagnostic for BD. Acute phase reactants are expected to be high during exacerbations especially in serositis, cerebral involvement and vasculitis. The main histopathologic finding in BD is occlusive vasculitis that is seen in the arterioles and veins [1,10]. HLA-B51 positivity is seen in 75% of the patients and pathergy positivity around 40%-70% of the patients [5,6,12,15,26]. HLA-B51 positivity was associated with male gender, higher risk of genital ulcers, ocular and skin involvement and decreased incidence of GI involvement [10]. Around 60%-80% of patients with parenchymal NBD have increased number of cells in the cerebrospinal fluid (CSF). CSF protein may be moderately high and glucose is expected to be normal. It was shown that patients with active parenchymal NBD have high CSF IL-6 levels that were normalized after treatment and persistently high CSF IL-6 levels may be a sign of chronic progressive parenchymal NBD [29]. Diagnosis The diagnosis of BD is clinical and a few diagnosis/classification criteria sets have been developed. All of them were developed for adult patients and had not been validated in children. Recently, a classification criteria set for pediatric BD has been developed [8]. The ISG (International Study Group) criteria was developed in 1990 (Table 1). The sensitivity of ISG criteria is 91%, and the specificity is 96% [40]. Recurrent oral aphthosis is the mandatory criterion in this set and patients with two additional criteria are called as complete BD, and patients with one additional criteria are termed as incomplete BD. This criteria set was developed to be used in clinical studies to include patients with definitive diagnosis of BD and has a few limitations. It does not include any major organ involvement and also BD disease patients without oral aphthosis, that constitute around 3% of all cases, could not have been diagnosed as having BD with ISG criteria. It was also observed that pathergy test positivity was decreased after 1980s because of increased sanitary conditions and use of sterile, finer, less traumatic needles [41]. To overcome these limitations, in 2014, ICBD (International Criteria for Behçet s Disease) scoring system was developed (Table 2) [42]. According to this scoring system, patients with 4 points are defined as having BD. Pathergy test is an optional criterion and if patient has pathergy positivity, then gets extra 1 point. The sensitivity of ICBD criteria is higher Table 1. International Study Group (ISG) criteria (adapted from reference 40). Recurrent oral ulcerations Plus 2 of the following Recurrent genital ulceration Eye lesion Skin lesions Positive pathergy test Minor aphthous, major aphthous, or herpetiform ulceration observed by doctor or patient, which recurred at least 3 times in one year Aphthous ulceration or scarring observed by physician or patient Anterior uveitis, posterior uveitis, or cells in vitreous, or retinal vasculitis Erythema nodosum observed by doctor or patient, pseudofolliculitis or papulopustular lesions, or acneiform nodules observed by doctor in postadolescent patients not on corticosteroids Test interpreted as positive by the doctor at hour DOI: /apr

7 73 Cakan M et al. Table 2. International Criteria for Behçet Disease (ICBD) criteria (adapted from reference 42). Signs/symptoms Points Oral aphthosis 2 Genital aphthosis 2 Ocular lesions 2 Skin lesions 1 Neurological manifestations 1 Vascular manifestaions 1 Positive pathergy test* 1 than ISG criteria and the aim of ICBD criteria was to diagnose and treat BD patients earlier. But, as would be expected, the specificity of ICBD criteria is lower than ISG criteria. It should be stressed again that ISG criteria were developed to be used in clinical trials to create a more homogenous group of established BD patients rather than individual diagnosis of a patient. [41]. Also in 2014, revised version of Japanese criteria was published. This is the most detailed criteria set and there are subgroups of patients according to organ involvement [41]. In 2016, pediatric BD classification criteria were developed by international collaborations (Table 3). The patient is classified as having pediatric BD if has at least 3 of the 6 items [8]. Differential Diagnosis The differential diagnosis of BD is broad. The diagnosis is difficult and mostly delayed in patients initially presenting with ocular, vascular, CNS, or GI symptoms and signs without having typical mucocutaneous findings of the disease [1]. Differential diagnosis of BD uveitis includes all infectious and non-infectious causes of uveitis. Bilateral involvement, recurrent panuveitis attacks with accompanying retinal vasculitis favor BD uveitis [43]. The major differential diagnosis in GI involvement is Chron s disease. The ulcers of BD tend to be punched-out circular mostly located in ileum and ulcers of Chron s disease are more longitudinal [38]. In patients presenting with thrombosis, differential diagnosis is vast and includes hereditary and acquired causes of thrombosis [35]. In patients with vascular manifestations, involvement of the veins and arteries of any size favor BD [1,35]. In some children, before the development of typical manifestations of BD recurrent fever attacks may be the only finding. So, BD should also be included in the differential diagnosis of children with periodic fever syndromes [1,37]. Treatment There is no any randomized controlled study that has been done in the treatment of pediatric BD. All treatment options that are being used in children are extrapolated from adult studies. The treatment of BD is directed according to major organ involvement. In 2008, EULAR (European League Against Rheumatism) has released recommendations for the treatment of BD that is still widely used and accepted as a major guideline by many authors [44]. Colchicine is the mainstay treatment of BD and is effective in reducing the frequency and intensity of oral and genital ulcers. Topical corticosteroid may be preferred during acute exacerbations of the ulcers. Erythema nodosum lesions generally respond well to colchicine treatment. Patients with resistant mucocutaneous manifestations may respond to azathioprine, thalidomide, interferon alpha, apremilast or TNF-α antagonists [1,10,44]. Azathioprine (2 mg/kg/day) is recommended as first Table 3. Classification criteria for pediatric Behçet disease (adapted from reference 8). Item Description Value Recurrent oral aphthosis At least 3 attacks/year 1 Genital ulceration or aphthosis 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 Annals of Paediatric Rheumatology Year 2017 Volume:6 Issue:

8 Pediatric Behçet Disease 74 option in the treatment of BD uveitis. Addition of systemic corticosteroids is recommended if posterior uveitis is present [1,44]. In Japan colchicine is recommended as first line therapy in non-severe uveitis. If patient does not respond to colchicine addition of cyclosporine A (5 mg/kg/day) is recommended [45]. According to EULAR recommendations, if a patient has severe uveitis, that is defined as >2 lines of drop in visual acuity on a 10/10 scale and/or retinal disease (retinal vasculitis or macular involvement), it is recommended that either cyclosporine A or infliximab be used in combination with azathioprine and corticosteroids. Alternatively IFN-α could be used with or without corticosteroids [44]. In patients resistant to these medications adalimumab or gevokizumab (humanized IL-1 antagonist) may be used [1]. The highest risk of BD uveitis is the next 2-4 years after diagnosis. It is recommended by some authors that young men with newly diagnosed BD should receive azathioprine prophylactically to prevent the development of uveitis. But this is not a universally accepted approach [44,45]. In the treatment of acute deep vein thrombosis immunosuppression with corticosteroids, azathioprine, cyclophosphamide or cyclosporine A is recommended. In cases of major vessel involvement like Budd-Chiari syndrome, superior vena cava thrombosis, pulmonary artery aneurysm, or main artery aneurysms combination of azathioprine and monthly cyclophosphamide infusions are recommended [44]. Open surgical interventions may end with graft occlusion, pseudoaneurysm formation at anastomosis points, so endovascular surgical interventions are recommended if a vascular surgery is planned [35]. Thrombosis in BD is secondary to vessel wall inflammation and adheres to vessel wall tightly so embolization of the thrombus is not a usual finding. Use of anti-coagulant, anti-aggregant or anti-fibrinolytic medications is not recommended in BD thrombosis. Existing pulmonary artery aneurysm is a definite contraindication for anticoagulation that may lead to fatal pulmonary hemorrhage (44). In GI involvement corticosteroids, sulfasalazine, azathioprine, TNF-α antagonists (adalimumab, infliximab), and thalidomide are used [44]. Colchicine may exacerbate diarrhea and abdominal pain in patients with GI involvement. The dose should be reduced or totally discarded if patient can not tolerate colchicine [38]. It was shown that thalidomide has anti-inflammatory and immunomodulatory effects. This drug started to be used in resistant cases of cutaneous lupus erythematosus, tuberculosis, IBD. Thalidomide is also an option in BD for resistant cases with mucocutaneous and GI manifestations. But, due to both acute and long term side effects, like peripheral neuropathy and teratogenicity, extreme precaution and monitoring should be done [46,47]. Colchicine is effective in the control of musculoskeletal symptoms. In patients with severe and resistant arthritis azathioprine, IFN-α or TNF-α antagonists may be used [44]. Parenchymal NBD should be treated with 3-7 days of high-dose methylprednisolone followed by 2-3 months of oral prednisolone. To prevent recurrences or progression, weekly methotrexate is a good alternative. In resistant cases monthly cyclophosphamide infusions, azathioprine, IFN-α or TNF-α antagonists (adalimumab, infliximab, etanercept) may be alternatives. Short term corticosteroid treatment generally shows satisfactory results in dural sinus thrombosis [44]. Cyclosporine A has neurotoxic effects and may worsen the manifestations of CNS involvement. It is not recommended to be used in BD patients with any neurological involvement [29,44]. If a patient is using cyclosporine for uveitis or other indications and symptoms of NBD develops, cessation of cyclosporine A is strongly recommended [29]. If a patient has both uveitis and NBD and uveitis could only be controlled by cyclosporine or intolerant to other medications, then continuing with cyclosporine is recommended [44]. Prognosis Behçet disease follows a chronic course with acute exacerbations and remissions. The worst clinical course is expected to be seen in young men. The symptoms of the disease tend to wane by aging. The most important and common cause of morbidity is due to ocular involvement. Another important cause of morbidity and mortality is chronic progressive parenchymal NBD (1,41). The highest risk of mortality is seen in patients with major vessel involvement. Pulmonary artery aneurysms, aortic aneurysms, Budd-Chiari syndrome, superior or inferior vena cava thromboses are the main reasons of mortality [1,41]. The DOI: /apr

9 75 Cakan M et al. rate of mortality in pulmonary artery aneurysms is around 26%, even with intense immunosuppressive treatment. Intercurrent opportunistic infections are also an important cause of mortality [41,48]. Conclusion Behçet disease is one of the diseases that is highly endemic in our country. The diagnosis is based on the combination of the clinical manifestations. The main problem in the diagnosis of BD is that, the most common initial manifestation of the disease, recurrent oral aphthosis, is also highly common in healthy population. But recurrent oral aphthosis per se is not enough to make diagnosis of BD so every pediatrician should be aware of clinical findings of BD and refer to pediatric rheumatologists in suspected cases. Conflict of interest: None of the authors received financial support and there are no potential conflicts of interest. Funding: No source of funding for this work. References 1. Ozen S. Behçet Disease. In: Petty RE, Laxer RM, Lindsey CB, Wedderburn LR (eds). Textbook of Pediatric Rheumatology, 7th edn. Elsevier, Philadelphia, pp , Behçet H. Uber rezidivierende, aphthose, dürch ein Virus versachte Geshwure am Munde, am Auge und an den Genitalien. Dermatoogishche Wochenschrift 1937; 36: Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013; 65: Sakane T, Takeno M, Suzuki N, Inaba G. Behcet s disease. N Engl J Med 1999; 341: Hatemi G, Yazici Y, Yazici H. Behcet s syndrome. Rheum Dis Clin North Am 2013; 39: Karincaoglu Y, Borlu M, Toker SC, Akman A, Onder M, Gunasti S. Demographic and clinical properties of juvenile-onset Behçet s disease: A controlled multicenter study. J Am Acad Dermatol 2008 ;58: Sarica R, Azizlerli G, Köse A, Dişçi R, Ovül C, Kural Z. Juvenile Behçet s disease among 1784 Turkish Behçet s patients. Int J Dermatol 1996; 35: Koné-Paut I, Shahram F, Darce-Bello M, Cantarini L, Cimaz R, Gattorno M, et al; PEDBD group. Consensus classification criteria for paediatric Behçet s disease from a prospective observational cohort: PEDBD. Ann Rheum Dis 2016; 75: Ozen S, Eroglu FK. Pediatric-onset Behçet disease. Curr Opin Rheumatol 2013; 25: Koné-Paut I. Behçet s disease in children, an overview. Pediatr Rheumatol Online J 2016; 14: Fresko I, Soy M, Hamuryudan V, Yurdakul S, Yavuz S, Tümer Z, et al. Genetic anticipation in Behçet s syndrome. Ann Rheum Dis 1998; 57: Koné-Paut I, Darce-Bello M, Shahram F, Gattorno M, Cimaz R, Ozen S, et al. Registries in rheumatological and musculoskeletal conditions. Paediatric Behçet s disease: an international cohort study of 110 patients. One-year follow-up data. Rheumatology 2011; 50: Panicker JN, Vinayan KP, Ahsan Moosa NV, Elango EM, Kumar AA. Juvenile Behçet s disease: highlighting neuropsychiatric manifestations and putative genetic mechanisms. Clin Neurol Neurosurg 2007; 109: de Menthon M, Lavalley MP, Maldini C, Guillevin L, Mahr A. HLA-B51/B5 and the risk of Behçet s disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum 2009; 61: Kötter I, Günaydin I, Stübiger N, Yazici H, Fresko I, Zouboulis CC, et al. Comparative analysis of the association of HLA-B*51 suballeles with Behcet s disease in patients of German and Turkish origin. Tissue Antigens 2001; 58: Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R- IL12RB2 regions associated with Behçet s disease. Nat Genet 2010; 42: Kirino Y, Bertsias G, Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, et al. Genome-wide association analysis identifies new susceptibility loci for Behçet s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 2013; 45: Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Annals of Paediatric Rheumatology Year 2017 Volume:6 Issue:

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