Introduction
Behçet’s disease (BD) [
1] is a chronic multisystem vasculitis characterized by recurrent oral and genital ulceration, uveitis, cutaneous, articular, neurological and gastrointestinal involvement [
2‐
8]. There are currently no universally recognised pathognomonic tests or biomarkers for BD disease activity, and thus diagnosis and disease monitoring require astute clinical acumen [
9]. Although the usual onset of disease is between the second and fourth decade, there has been an increased awareness of BD during childhood [
10‐
12]. Children account for 7.7–26.4 % of the reported prevalent cases of BD outside the UK [
1,
3]. In one UK study, only one paediatric BD case was identified in a population of 1.1 million children [
13]. Thus, due to the rarity of the condition and its non-specific presentation, the diagnosis of BD is challenging for paediatricians, and diagnostic delay of several years is common. This may lead to irreversible complications such as blindness, neurological injury and other end-organ damage.
There are several sets of criteria for the diagnosis and/or classification of BD [
9]; none have been validated in children. The most widely used for adult onset disease are the International Behçet’s Study Group (ISG) criteria (Supplementary Table
1); these are considered to have suboptimal sensitivity for the classification or diagnosis of BD in adults, however [
14]. Recently, International Criteria for Behçet’s Disease (ICBD) have been validated in adults (Supplementary Table
2) [
7] with 94.8 % sensitivity and 90.5 % specificity. In comparison, the ISG criteria are 81 % sensitive and 96 % specific for the diagnosis of BD [
7]. It is suggested therefore that the ICBD criteria should be used as the gold standard [
7,
9]. There are currently no data in relation to the performance of the ICBD criteria in paediatric patients.
There is also a lack of evidence base for treatment of BD, particularly in children [
15]. Notably, the vast majority of published paediatric series come from countries where BD is prevalent; consequently, the clinical phenotype and burden of disease is not well described for the UK-based paediatric population, and is likely to differ given established differences in genetic background and environment.
The primary aim of this study was to describe the clinical spectrum, therapy and outcome of children with BD presenting to a large tertiary paediatric referral centre based in the UK and compare with other international paediatric series. A secondary aim was to explore the relative sensitivities of the ISG and ICBD criteria for the diagnosis of BD in this paediatric cohort.
Discussion
We describe the largest single-centre UK paediatric cohort of BD which suggests differences compared with studies involving Asian or Turkish children (Table
4). In addition, for the first time, we retrospectively examined the diagnostic sensitivity of the ICBD criteria in children. Patients in our study had early onset of disease at 4.87 years of age (median; range 0.04–15.71), and 17 % had a positive family history. The clinical presentation was varied and broad. Table
4 summarises the clinical phenotype of our UK-based paediatric cohort compared to other paediatric series [
8,
19‐
22]. We observed less ocular involvement, and no posterior/panuveitis; less vascular disease; and less cutaneous disease. Gastrointestinal and neurological involvement was more frequent compared to non-UK cohorts. We noted a significant diagnostic delay up to 13.5 years. This is unfortunately common in children with BD [
19], due to the insidious nature of the disease and an overall lack of awareness of BD. These differences could impact on choice of immunomodulatory therapy used since.
Table 4
Comparison of present UK study cohort to other published studies on childhood Behçet’s disease
Present study | 46 | 1:1.09 | 4.87 | 97.8 | 74 | 32.6 | 8.7 | 60a
| 52 | 58.7 | 32.6 | 6.5 |
Koné-Paut et al. (21; International) | 110 | 1:0.96 | 8.2 | 83 | 61 | 57 | 33.9 | 44.7 | N/A | 26 | 29.3 | 13 |
P value | | 0.8608 | | 0.0082 | 0.1434 | 0.0081 | 0.0012 | 0.6569 | | 0.0002 | 0.7038 | 0.3984 |
Kitaichi et al. (20, Japan) | 135 | 1:0.53 | 11.7 | 94.8 | 53.5 | 67.4 | 29 | N/A | N/A | N/A | N/A | N/A |
P value | | 0.0537 | | 0.6816 | 0.0157 | 0.0001 | 0.0048 | | | | | |
Kim et al. (19; Korea) | 40 | 1:1.5 | 10.6 | 100 | 82.5 | 72.5 | 27.5 | N/A | 27.5 | 5 | 2.5 | N/A |
P value | | 0.5183 | | 1.000 | 0.4370 | 0.0003 | 0.0259 | | 0.0001 | 0.0278 | 0.0002 | |
Karincaoglu et al. (8; Turkey) | 83 | 1:1.18 | 12.3 | 100 | 81.9 | N/A | 34.9 | 37 | 39.8 | 4.8 | 7.2 | 16.8 |
P value | | 0.8554 | | 0.3566 | 0.3664 | | 0.0013 | 0.3703 | 0.1980 | 0.0001 | 0.0003 | 0.1110 |
Lang et al. (22; Canada) | 37 | 1:0.947 | 8.7 | 100 | 75 | 84 | 30 | N/A | 54 | 40 | 32 | 16 |
P value | | 0.8267 | | 1.0000 | 1.0000 | 0.0001 | 0.0204 | | 1.0000 | 0.1244 | 1.0000 | 0.1783 |
Interestingly, only 8.7 % of the children had ocular involvement in our series and none had sight threatening disease with posterior or panuveitis; this contrasts with the high frequency of 33.9 % reported in an international study [
21] and 42 % in Israeli children [
23]. We speculate whether this could arise from genetic differences between our predominantly Caucasian population and non-UK cohorts. We also noted an increased frequency of genital ulceration in female patients (Supplementary Table
3).
We demonstrated the limitations of the ISG diagnostic criteria: only 17.4 % of our patients met these criteria at presentation to our centre. Similarly, in a previous multicentre paediatric study of BD, only 42 % fulfilled the ISG criteria as complete cases [
21]; the authors proposed that age of puberty should be included as a parameter for definite BD as genital ulceration that usually starts after puberty; we were unable to assess this in our retrospective study since pubertal status was not assessed systematically. We demonstrated much higher sensitivity (80.4 %, 95 % CI 67–93 %; Table
2) of the ICBD diagnostic criteria compared to the ISG criteria at the time of clinical diagnosis. We did not study the specificity of the ICBD criteria, as this would require a disease control population comprising patients with important mimics of BD, such as periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) amongst others (Supplementary Table
4). Whilst many experienced clinicians may not rely on such criteria for the diagnosis of BD in routine practice, such criteria are important for epidemiological and clinical studies. For instance, in the UK, a multi-centre collaborative study from the British Paediatric Surveillance Unit (BPSU) regarding the epidemiology and clinical phenotype of paediatric BD is now underway, and is using the ICBD criteria to define BD cases.
We explored the utility of the prototypic BDAI score for the first time in children in an attempt to systematically assess disease activity and response to therapy. We emphasise however, that retrospective scoring may be unreliable, and is therefore a limitation of our study. That said, this scoring system at least provides a systematic way of collecting such data retrospectively. BDAI scores significantly improved after treatment, and therefore could be an important tool for clinicians to monitor the BD disease course and should be now prospectively validated in paediatric patients.
Patients in our study were treated with a variety of therapeutic agents. The majority (93.5 %) of our patients required systemic therapy. Thalidomide-induced peripheral neuropathy occurred in 6/13 patients who received this; thus, less toxic therapeutic agents should be considered first. We used anti-TNFα treatment in severe/refractory cases (15.5 % of patients), an approach reported to be effective in adult studies [
24]. More recently, IL-1 blockade has been highlighted as potentially useful [
25], but we have not yet used this approach, nor interferon-α [
26] for BD in children at our institution.
Overall, the prognosis for BD in our series was good. No child died; we did not observe any fractures; median final Z score for height, weight and body mass index at last follow-up was −0.49, −0.1 and 0.28, respectively. Despite these encouraging hard endpoints, the fact that 87 % of patients were still on treatment, emphasises that BD is a lifelong chronic disease.
Our study was limited by all the confounding factors associated with any single-centre retrospective series of patients with a rare disease. There is a possibility that referral bias resulted in us receiving the most severe cases. Pathergy and HLA B51 testing was not routinely performed. Importantly, we were unable to assess quality of life and any changes associated with treatment, an area of concern for patients with BD [
27], and for understanding the heath economics of BD and its treatment in the young.
In summary, we present the largest UK-based single-centre series of children with BD, showing a distinctive clinical phenotype in this population. We observed less ocular involvement, less vascular disease, and less cutaneous disease. Gastrointestinal and neurological involvement was more frequent compared to non-UK cohorts. Colchicine appears to be an effective treatment; anti-TNFα treatment was used for refractory cases and has now largely superseded the use of thalidomide in our institution. Further prospective multicentre national studies using paediatric research networks such as the BPSU are currently underway, and will further characterise the epidemiology and clinical phenotype of BD in UK children, and could provide prospective data on whether any phenotypic differences influence choice of therapy. Lastly, whether these observed differences persist into adulthood remains to be determined, and will require long-term cohort studies. In the meantime, studies comparing children and adults with BD in the UK could help explore whether there are true differences between childhood and adult onset BD in the UK.
Abbreviations
BD, Behçet’s disease; BDAI, Behçet’s disease activity index; BMI, body mass index; CRP, C-reactive protein, BPSU, British Paediatric Surveillance Unit; DEXA, dual energy X-ray absorptiometry; ESR, erythrocyte sedimentation rate; FN, false-negative; GU, genital ulceration; GI, gastrointestinal; HLA, human leukocyte antigen; ICBD, International Criteria for Behçet’s disease; IL, interleukin; ISG, International Study Group; NS, nervous system; OU, oral ulceration; PFAPA, periodic fever, aphthous stomatitis, pharyngitis and adenitis; TNF, tumor necrosis factor; TP, true positive; UK, United Kingdom; VP, ventriculo-peritoneal.