Introduction and Historical Review
In 1937, the Turkish dermatologist Hulusi Behçet described the syndrome that bears his name, which manifests with the clinical triad of aphthous stomatitis, genital ulceration, and uveitis. Superficial thrombophlebitis was identified as the fourth criterion in 1946. Matteson identified even earlier reports of this condition, including those from Japan. The history of Behçet disease (BD) has been reviewed by Kaklamani and colleagues.
Definitions and Classifications
In the nomenclature of the revised Chapel Hill Consensus Conference (CHCC 2012), BD is described as a vasculitis that can affect arteries or veins of any size, and is characterized by recurrent oral and/or genital aphthous ulcers accompanied by cutaneous, ocular, articular, gastrointestinal, and/or central nervous system inflammatory lesions.
Several sets of diagnostic criteria have been proposed. Those of the International Study Group (ISG) are most widely used and are listed in Table 40-1 . If only one of the criteria is present along with recurrent oral ulcerations, the term incomplete Behçet disease is applied. Criteria proposed by Mason and Barnes ( Table 40-2 ) and O’Duffy and Goldstein emphasize the broader spectrum of disease. The ISG criteria have a specificity of 96% and sensitivity of 91%; the Mason and Barnes criteria have a specificity of 84% and sensitivity of 86%. All criteria have been applied to the diagnosis of BD in children, although none have been validated in this age group.
| CRITERION | DESCRIPTION |
|---|---|
| Recurrent oral ulceration | Minor aphthous, major aphthous, or herpetiform ulceration recurring at least three times in one 12-month period, observed by physician or patient |
| Plus two of the following: | |
| Recurrent genital ulcers | Aphthous ulceration or scarring observed by physician or patient |
| Eye lesions | Anterior uveitis, posterior uveitis, or cells in vitreous on slit-lamp examination, or retinal vasculitis observed by an ophthalmologist |
| Skin lesions | Erythema nodosum observed by physician or patient; pseudofolliculitis or papulopustular lesions; acneiform nodules observed by physician in postadolescent patient not on corticosteroid treatment |
| Pathergy | Skin reaction to a needle prick observed by physician 24-48 hours afterward |
| MAJOR CRITERIA * | MINOR CRITERIA |
|---|---|
| Buccal ulceration | Gastrointestinal lesions |
| Genital ulceration | Thrombophlebitis |
| Eye lesions | Cardiovascular lesions |
| Skin lesions | Arthritis |
| Central nervous system lesions | |
| Family history of Behçet disease |
* Diagnosis requires the presence of at least three major criteria or two major plus two minor criteria.
Epidemiology
Incidence and Prevalence
The occurrence of BD varies markedly throughout the world. The highest prevalence occurs along the historical route of the Silk Route from Japan to the eastern edge of the Mediterranean Sea and through areas of the former Ottoman Empire. However, BD is by no means confined to these areas. It is rarely reported in children from India, and more commonly identified in children from Europe and North America, reflecting emigration patterns in the 20th century. A recent report from France showed that among adult vasculitides, BD was much more common than expected, with higher frequencies than those for other rare vasculitides. BD is undoubtedly more common in Turkey and other parts of the Middle East, where an overall prevalence of 1 in 250 persons has been reported, compared with a prevalence of fewer than 1 in 100,000 persons in the UK. Ozen and co-workers have proposed that the prevalence in children is not more than 10 cases per 100,000 in Turkey. The frequency of BD in French children younger than 15 years of age is approximately 1 case in 600,000. One third were of North African origin.
Several reviews document BD in childhood and adolescence. An international study of the clinical features of BD in 86 children from France, Turkey, Iran, and Saudi Arabia used the ISG criteria. Eighteen Greek children who met the ISG criteria for BD were described by Vaiopoulos and colleagues in 1999. There have also been series reported from Greece, Saudi Arabia, Turkey, Korea, Japan, and Israel. Recently a large international registry has been established to assess the pediatric features and develop new criteria for children.
Sex Ratio and Age at Onset
In most series, boys and girls are affected with equal frequency, in contrast to BD in adults, in which men are affected almost twice as frequently as women. The age at onset of disease ranges widely. Overall, 5.4% to 7.6% of all patients experience onset of BD in childhood. BD has been reported in neonates born to mothers with BD and in one newborn with no maternal history of the disease.
Genetic Background
There is substantial evidence supporting the genetic basis for BD. The increased sibling and twin recurrence rate, familial cases, the high frequency of the disease among people along the historic Silk Road, and evidence for genetic anticipation all support genetic contribution in the pathogenesis. In an international study of BD in European children, 12.3% had a family member with the disease, suggesting a genetic burden in early-onset BD. The frequency of BD among North African immigrants to France was comparable with rates reported from North Africa and Asia, and was not related to age at immigration.
The human leukocyte antigen (HLA) molecule B*5101 is the strongest genetic association with BD. It is likely that B51 confers significant risk (odds ratio [OR] 3.49-5.78), particularly in patients with a family history of the disease. Large genome-wide association studies (GWAS) have further shown an association with interleukin (IL)-10 and IL23R/IL12RB2 genes. IL-10 is an antiinflammatory cytokine, whereas IL-23 is crucial for the inflammatory Th17 pathway. In order to identify further susceptibility loci in BD, a cohort of 1209 Turkish patients was reevaluated with a GWAS of 779,465 single nucleotide polymorphisms (SNPs). This analysis identified new associations, such as STAT4 (a transcription factor in a signaling pathway related to cytokines such as IL-12, type I interferons [IFNs] and IL-23) and two SNPs in endoplasmic reticulum aminopeptidase (ERAP1)1 that were confirmed in different ethnic groups. Furthermore, an epistatic interaction with ERAP1 and major histocompatibility complex (MHC) class I region was identified: homozygosity for the putative ERAP1 conferred a threefold risk in HLA-B51 positive patients, whereas the risk was 1.48 for those who were HLA-B51 negative. It is interesting that persons of Japanese origin living in the United States, or those of Turkish origin living in Germany, have been reported to have a lower incidence of BD than persons living in Japan or Turkey. This suggests an environmental impact on the genetic predisposition.
Etiology and Pathogenesis
The cause of BD is not known. Microbial agents have been suggested that trigger the disease through inducing an aberrant immune response in a genetically predisposed individual. Evidence for a microbial cause of BD is reviewed by Verity and colleagues. Lehner has suggested that immunity to microbial heat-shock proteins that share homology with human 65 kD mitochondrial heat-shock protein may be important in pathogenesis. There are several studies suggesting a role for herpes simplex virus type 1, parvovirus B19, and streptococci; however, no microbial cause has been established.
In addition to the evidence for involvement of the adaptive immune system, neutrophils and the inflammation mediated by the innate immune also play a major role in BD. The involvement of the innate immune system, the absence of autoimmune features, and the episodic nature of the disease course has led to the suggestion that BD as an autoinflammatory disease of multifactorial origin.
The genetic findings provide new insight in the pathogenesis of the disease. HLA-B51 is known to have a low affinity for peptides and may therefore have a larger peptide repertoire. In fact the long-standing suggestions of the role of triggering infections may be linked to the behavior of HLA-B51 (see below). Recent data summarized by Gül and Ohno suggest that the slow folding of HLA-B51 loaded with a peptide may play a critical role just as suggested for HLA-B27 in ankylosing spondylitis (AS). ERAP1, an endoplasmic reticulum–expressed aminopeptidase, functions in processing and loading of peptides onto MHC class I molecules. When HLA class I molecules bind the peptide of the microbe, they need to fold. Unfolded protein response (UPR) leads to endoplasmic stress and the triggering of inflammation through the IL-23/IL-17 pathway in BD. ERAP is also associated with the pathogenesis of AS, and misfolding of HLA-B27 has been shown to activate the IL-23/IL-17 axis. Furthermore, a number of studies in sera and cell culture of BD patients have clearly shown that IL-17 is important in the inflammation of BD. Thus the presence of the critical SNPs in ERAP1 may lead to an unfolded protein response of HLA-B51, with the trigger of a variety of infectious agents leading to an inflammation led by Th17 cells.
Clinical Manifestations
One of the most characteristic features of the disease is the heterogeneity of the clinical presentation. The clinical presentations differ among geographies: gastrointestinal disease is increased in patients from Asia, and vascular disease is more common among those from the Middle East and the eastern Mediterranean. Symptoms tend to occur in clusters, such as, for example, the acne/arthritis/enthesitis cluster or the vasculitis cluster (venous thrombi and pulmonary arterial disease), suggesting that more than one pathological pathway is involved. The heterogeneity of BD poses problems not only in classification of the disease, but in genetic and treatment studies as well.
The clinical manifestations of BD often emerge over a period of several years. In a study of 40 Korean children, the mean interval between the first and the second major manifestations was 7 years. The usual course of BD in any organ system is that of exacerbations and remissions, with the overall activity generally declining with time. The frequencies of the major and minor manifestations are given in Table 40-3 .
| CRITERIA (%) | ||||||||
|---|---|---|---|---|---|---|---|---|
| STUDY | N | M : F | ONSET (AGE) | OU | GU | SKIN | UVEITIS | PATHERGY |
| Lang et al. | 37 | 19 : 18 | 8.7 | 100 | 75 | 84 * | 30 | ? |
| Bahabri et al. | 12 | 7 : 5 | 11.5 | 100 | 65 | 83 * | 92 | 57 |
| Koné-Paut et al. | 65 | 33 : 32 | 8.4 | 100 | 96 | 92 * | 45 | 80 |
| Eldem et al. | 20 | 15 : 5 | 15.1 | 100 | 65 | 35 * | 80 | ? |
| Kim et al. | 40 | 16 : 24 | 10.6 | 100 | 82 | 72 * | 27 | ? |
| Fujikawa and Suemitsu | 31 | 14 : 17 | ||||||
| Uziel et al. | 15 | 7 : 8 | 6.6 * | 100 | 33 | 100 * | 53 | 40 |
| Total | 220 | 111 : 109 | ||||||
Mucocutaneous Disease
Most BD patients have oral ulceration; it usually occurs at disease onset and may persist for much of the course of the disease. Crops of extremely painful ulcers appear on the lips, tongue, palate, and elsewhere in the gastrointestinal tract ( Fig. 40-1 ). They last for 3 to 10 days (sometimes longer), recur at various intervals, and heal without scarring. The exception to this is neonatal disease, in which extensive scarring may result. Recurrent, painful ulcerations of the glans penis, prepuce, scrotum, and perianal area in the male, and of the vulva and vagina in the female are characteristic. These ulcers usually occur after oral ulcers and may heal with scarring, unlike oral ulcers.
Other skin lesions occur in more than 90% of children with BD. These include erythema nodosum, purpura (which may be palpable), papulopustular (acneiform) lesions, ulcers, or folliculitis. Pathergy, an unusual cutaneous pustular reaction occurring 24 to 48 hours after a needle puncture of the dermis, is highly characteristic but not pathognomonic of the syndrome ( Fig. 40-2 ). Pathergy test positivity varies considerably from one series to another and occurs most commonly (50% to 70%) in patients from the Middle East.
Ocular Disease
Eye lesions occur in 30% to 61% of children with BD. The typical eye involvement is in the form of a chronic relapsing bilateral posterior and anterior uveitis. The basic retinal lesion is a vasculitis. In a series of 20 children, posterior uveitis was the most common ocular manifestation, occurring in 11 patients, although anterior uveitis occurred in 3 patients, and 2 had papilledema. BD should be considered in the differential diagnosis of a child presenting with isolated anterior uveitis. The eye may be painful and red. Hypopyon may occur, and severe uveitis may lead to blindness. In older studies, it was reported that blindness was common in untreated patients. Complications may include glaucoma and cataracts. Corneal ulceration, cystoid macular edema, retinal vasculitis, retinal detachment, and retrobulbar neuritis are rare events. Ocular disease is much more common in boys than girls.
Central Nervous System Disease
The reported frequency of central nervous system (CNS) disease in children varies from 5% to 15% ( Fig. 40-3 ). It may be parenchymal or nonparenchymal (vascular). Neurologic involvement may present as an encephalomyelitis (e.g., pyramidal, extrapyramidal, cerebellar, spinal cord abnormalities, seizures) or aseptic meningitis. The nonparenchymal involvement is usually a benign intracranial hypertension with papilledema and is often due to dural sinus thrombosis. Several of the neurologic manifestations may occur simultaneously. The most common CNS disorder in adults is meningoencephalitis with headache and pleocytosis of the cerebrospinal fluid. In children, however, cerebral venous sinus thrombosis is most common.
