Clinical Immunology Review Series: An approach to the patient with recurrent orogenital ulceration, including Behçet's syndrome

Authors


  • Series Originator: Edward Kaminski Series Editor: Stephen Jolles

M. Keogan, Consultant Immunologist, Department of Immunology, Beaumont Hospital, Beaumont Road, Dublin 9, Ireland.
E-mail: marykeogan@beaumont.ie

Summary

Patients presenting with recurrent orogenital ulcers may have complex aphthosis, Behçet's disease, secondary complex aphthosis (e.g. Reiter's syndrome, Crohn's disease, cyclical neutropenia) or non-aphthous disease (including bullous disorders, erythema multiforme, erosive lichen planus). Behçet's syndrome is a multi-system vasculitis of unknown aetiology for which there is no diagnostic test. Diagnosis is based on agreed clinical criteria that require recurrent oral ulcers and two of the following: recurrent genital ulcers, ocular inflammation, defined skin lesions and pathergy. The condition can present with a variety of symptoms, hence a high index of suspicion is necessary. The most common presentation is with recurrent mouth ulcers, often with genital ulcers; however, it may take some years before diagnostic criteria are met. All patients with idiopathic orogenital ulcers should be kept under review, with periodic focused assessment to detect evolution into Behçet's disease. There is often a delay of several years between patients fulfilling diagnostic criteria and a diagnosis being made, which may contribute to the morbidity of this condition. Despite considerable research effort, the aetiology and pathogenesis of this condition remains enigmatic.

Introduction

The term aphtha means ulcer, and is used to describe areas of ulceration on mucous membrances. An aphthous ulcer (also known as a canker sore) is a painful mouth ulcer, resulting from a break in the mucous membrane. Recurrent aphthous stomatitis (RAS) affects up to 25% of the general population [1]. Complex aphthosis describes almost constant oral aphthous ulceration or recurrent oral and genital aphthae [2], and may represent a forme fruste of Behçet's disease (BD) [3]. BD is a multi-system vasculitis of unknown aetiology. There is no diagnostic test for BD; hence, the diagnosis relies on clinical criteria. Diagnostic clinical features are rarely present at the onset of disease and therefore BD should be considered in patients diagnosed previously with RAS or complex aphthosis on development of potentially related clinical problems. The purpose of this review is to summarize the clinical features and differential diagnosis of patients presenting with recurrent orogenital ulceration. Additionally, an approach to management of complex aphthosis or Behçet's syndrome is outlined.

Recurrent aphthous stomatitis

The RAS is not associated generally with systemic disease. Typically, ulcers are round or ovoid, with a tan–grey pseudomembranous base and an erythematous halo. Painful ulcers usually appear first in childhood, and a small number of bouts of ulcers each year are interspersed with distinct ulcer-free periods, tending to abate in adult life. RAS describes aphthous ulcers in the absence of systemic disease; however, clinically identical ‘aphthous-like ulcers’ may be seen in a variety of disorders [1], either alone or together with genital ulcers (Table 1).

Table 1.  Causes of oral ulceration and orogenital ulceration.
 Recurrent oral ulcers – genital ulceration not reported or very rareRecurrent oral or orogenital ulceration
  1. CMV, cytomeglovirus; HIV, human immunodeficiency virus; NSAID, non-steroidal anti-inflammatory drug; PFAPA, periodic fever, aphthous ulcers, pharyngitis, adenopathy; SLE, sytemic lupus erythematosus.

UnknownRecurrent oral stomatitis
PFAPA
Familial Hibernian fever
Complex aphthosis
Multi-system, immune-mediated diseaseSLEBehçet's syndrome
Reiter's syndrome
Mouth and genital ulcers with inflamed cartilage (MAGIC)
GastrointestinalUlcerative colitis
Coeliac disease
Other malabsorption states
Crohn's disease
NutritionalIron, B12 and folate deficiency 
Dermatological Sweet's syndrome
Erythema multiforme
Bullous skin disease
Erosive lichen planus
Fixed drug reaction
InfectionHIV
Chickenpox
Hand, foot and mouth disease
CMV (in immunocompromised patients)
Herpes simplex (HSV1)
Drug reactionNicorandil (anal ulcers also reported)
Bisphosphonates
NSAID
Haematological Cyclical neutropenia
Lymphoma

Aphthous ulcers may be subdivided into minor, major and herpetiform aphthous ulceration. More than one type of aphthous ulcer may be present in an individual patient.

  • • Minor aphthae, seen in 80% of patients, are less than 5–10 mm, usually affect the buccal or labial mucosa and heal within 7–10 days without scarring.
  • • Major aphthae are larger and deeper, located on freely moving mucosa, as well as soft palate, tonsils, pharynx or tongue, and heal over several weeks, often with scarring.
  • • Herpetiform aphthae are 1–3 mm, occur in groups that may coalesce, are negative for herpes simplex, involve the tongue and palate as well as non-keratinised mucosa and heal over 1–4 weeks.

The pattern of aphthous ulceration is not a reliable guide to underlying causes when these are present.

Reversible causes of ulceration must be excluded. Single ulcers, recurring in the same place, may be caused by trauma, and dental review may solve the problem. Iron, vitamin B12 or folate deficiencies lead to thinning of the oral mucosa and ulceration. Routine administration of supplements to patients with RAS is not indicated; however, correction of documented deficiency may be helpful. Coeliac disease is associated with aphthous-like ulceration, which may may preceed frank enteropathy [4] and resolve with a gluten-free diet.

Many patients referred for assessment of oral ulcers and possible BD have non-aphthous oral disease, including lichen planus, traumatic ulceration, erythema multiforme and bullous pemphigus or pemphigoid, which may be limited to mucosa. Ulcers persisting for > 6 weeks [5], oral swellings lasting > 3 weeks or red or white patches of oral mucosa require evaluation for oral malignancy. Suspicion of malignancy is heightened in males, those aged over 45 years and with heavy tobacco or alcohol use [6].

Most patients with RAS will never develop associated disease; however, oral ulceration alone resembling RAS is the most common presenting manifestation of BD [7]. In those who develop BD subsequently, recurrent oral ulceration precedes the diagnosis of BD by an average of 6–7 years [7,8]. Hence, in patients with RAS, the differential diagnosis of any new clinical problem must include BD.

Complex aphthosis

Complex aphthosis may be idiopathic, or secondary to conditions listed in Table 1. Diagnosis requires [2]:

  • • almost constant presence of three or more oral ulcers; or
  • • recurrent oral and genital ulcers; and
  • • exclusion of BD.

While ulceration may be almost constant, individual non-healing ulcers persisting over 3–6 weeks require review of the diagnosis, possibly including biopsy.

Diagnosis of primary (idiopathic) complex aphthosis requires focused work-up to exclude known causes of orogenital ulceration, including common causes summarized in Table 1.

No clinical or laboratory parameters predict reliably patients at risk of evolution to BD. Human leucocyte antigen-B51 (HLA-B51) is more prevalent in BD than in RAS or complex aphthosis [9]; however, the predictive value is inadequate to make individual therapeutic decisions. Patients with complex aphthosis should undergo periodic focused review to monitor for evolution into BD [2].

Behcet's disease

The BD was described by Hulushi Behçet in 1937 as a triad of oral ulcers (Fig. 1), genital ulcers and uveitis [10], but the concept of BD has expanded with the involvement of most organ systems now recognized [11,12]. BD is a systemic vasculitis which can involve arteries and veins of all sizes. The diagnostic features of BD may present over months or years, with different clinicians involved at various stages. Diagnosis is frequently delayed unnecessarily by several years, which may contribute to the morbidity of this condition [13]. A high index of suspicion when patients present with potential manifestations of the disease is crucial.

Figure 1.

Oral ulcers in Behçet's syndrome (photographs courtesy of Dr Jenny Hughes, Consultant Dermatologist, Dr Alun Evans Consultant Dermatologist, Princess of Wales Hospital, Bridgend, Wales and Dr Matthew Helbert, Consultant Immunologist, Manchester Royal Infirmary, UK).

Diagnostic criteria

Prior to 1990, several criteria for the diagnosis of BD existed, hampering comparison between studies. The International Study Group for BD evaluated 914 patients from seven countries deriving classification criteria for use in clinical research studies [14]. Agreed criteria were recurrent oral ulceration (three times in 1 year) together with two of the following in the absence of other clinical explanation: recurrent genital ulceration, ocular inflammation, defined skin lesions or a positive pathergy test (Table 2). While criteria were developed to facilitate research, several studies have validated their utility as diagnostic tools [15–17].

Table 2.  International Study Group criteria for the diagnosis of Behçet's disease [14].
Recurrent oral ulcerationMinor aphthous, major aphthous or herpetiform ulceration observed by the physician or patient that recurred at least three times in one 12-month period
Plus two of the following:
Recurrent genital ulcerationAphthous ulceration or scarring observed by the physician or patient
Eye lesionsAnterior uveitis, posterior uveitis, cells in the vitreous on slit-lamp examination or retinal vasculitis observed by an ophthalmologist
Cutaneous lesionsErythema nodosum observed by physician or patient; pseudofolliculitis or papulopustular lesions; or acneiform nodules observed by physician in post-adolescent patients not receiving corticosteroids
Positive pathergy testRead by the physician at 24–48 h
Findings applicable only in the absence of other clinical explanation

There are no diagnostic laboratory tests for BD, and laboratory findings typically reflect ongoing inflammation. Anaemia of chronic disease, elevation of immunoglobulins, particularly immunoglobulin A [18], together with an acute-phase response, may be found. C-reactive protein and erythrocyte sedimentation rate are usually elevated in patients with erythema nodosum, thrombophlebitis and arthritis, but are not elevated reliably in the central nervous system (CNS), ocular or mucocutaneous disease [19]. Other acute-phase reactants such as serum amyloid A are also elevated [20], with beta-2-microglobulin [20] and neopterin [21] elevated only in active systemic disease. Autoantibodies, including anti-neutrophil cytoplasm antibody, are occasionally positive but not of diagnostic value.

Oral ulcers

Recurrent mouth ulcers are a sine qua non of BD and may be identical to RAS, causing difficulty in eating, swallowing and speaking. Minor aphthae are seen in most patients, with major aphthae in approximately half, and herpetiform ulcers rarely [7]. More than one ulcer type may be present simultaneously. Patients with BD tend to have more ulcers (> 6 simultaneously), with more frequent crops, than in RAS [8,22]. BD patients have major aphthae more frequently (50%) than patients with RAS (9%) [23] and more involvement of the soft palate and oropharynx [22,24].

Genital ulcers

Genital ulceration is the second most common manifestation of BD, present in 57–93% of patients [25] and rarely (7·4% patients in one large study) are the presenting feature [7]. Ulcers may be preceded by a papule or pustule and appear similar to oral aphthae, but occur less often and scar frequently. Associated pain may cause difficulty with micturition, dyspareunia and even hinder walking [26]. In males, the scrotum is involved most commonly, although the shaft and glans penis may also be affected. In women, ulcers most commonly affect the labia, but vaginal and cervical ulcers occur and may be associated with vaginal discharge. Because ulcers are occasionally asymptomatic, patient assessment should include examination of genitalia for ulcers and scarring, even when symptoms are absent [24]. Ulcers in the groin, perineum and perianal area also occur.

Ocular disease

Ocular disease is seen in 30–70% of patients, and is more frequent and severe in men. Typically, ocular symptoms begin after recurrent oral ulceration; however; in 20% of patients ocular symptoms can be the presenting feature. In areas of high prevalence such as Japan, BD accounts for 20% of all uveitis.

Ocular disease is bilateral in 85% of cases and runs a relapsing course in 95% of patients [27]. Severity may differ between eyes. Panuveitis, posterior uveitis, anterior uveitis, retinal vasculitis, optic neuritis and retinal vein occlusion cause significant morbidity. Formation of a hypopyon, a visible layer of pus in the anterior chamber, is seen in 12% of patients, and rarely in other conditions [28]. Posterior uveitis carries a poor prognosis with poor visual acuity (less than 20/200 in the better eye) seen in between 8·8 and 39% of those with ocular disease [27].

Skin lesions

Cutaneous lesions included in diagnostic criteria are papulopustular lesions, acneiform lesions (post-adolescence in the absence of steroid therapy) and erythema nodosum [14]. Extragenital ulceration, superficial thrombophlebitis and cutaneous vasculitis are also described [24]. Cutaneous lesions are seen in about 80% of patients with BD.

Papulopustular lesions are sterile folliculitis or acneiform lesions, beginning as a papule on an erythematous base, evolving over 24–48 h to a pustule. While resembling acne, the distribution of lesions in BD is predominantly on the trunk, in contrast to non-BD lesions found mainly on the face [29].

Erythema nodosum-like lesions are seen in 30% of patients, mainly on the lower extremities but also on the face, neck and buttocks. Lesions rarely ulcerate, resolve within 2–3 weeks and can cause post-inflammatory hyperpigmentation. While clinically similar to classical erythema nodosum, lesions of BD differ histologically, with evidence of vasculitis [30].

Superficial thrombophlebitis is in seen in almost 50% of patients and may resemble the erythema nodosum-like lesions. Superficial thrombophlebitis lesions are arranged linearly, with nodules' location changing from day to day as different parts of vessels become involved. Thrombosis may lead to vessel sclerosis, detectable clinically as a string-like hardening in subcutaneous tissue, often with erythema of overlying skin [24].

Pathergy

Pathergy describes cutaneous hyperresponsiveness to trauma which, when elicited correctly, is quite specific for BD (Fig. 2). Positivity rates vary between populations, from 60–70% in Mediteranean countries to 5% in Caucasians [31,32]. Techniques used to elicit pathergy differ between studies, affecting the sensitivity and the intensity of response. After skin-cleansing with alcohol swabs, two or more large (20 G) needles are inserted subcutaneously (minimum depth 3 mm), a few centimetres apart, and read by the physician at 48 h [33]. Development of a papule or pustule at the site of insertion is considered positive, while erythema or a residual pin-prick mark is negative. Significant interobserver variability has been reported [34]. Use of a blunt, resterilized needle (no longer acceptable for infection control reasons) results in significantly greater sensitivity [33] and cleansing of the skin with povidone iodine or 100% chlorhexidine attenuates responses [34]. Discordant positivity (positive reaction at one of two sites, with a negative reaction at the other) is common [34] and reactivity varies within patients over time, with more positive results with active disease [35]. Histological and immunohistological assessment of pathergy has been suggested to be more reliable than clinical assessment [36]; however, the number of patients studied histologically is small, and concerns about poor wound healing mitigate against using biopsy as a standard approach.

Figure 2.

Pathergy in Behçet's disease (photographs courtesy of Dr Jenny Hughes, Consultant Dermatologist and Dr Alun Evans Consultant Dermatologist, Princess of Wales Hospital, Bridgend, Wales).

Central nervous system

The CNS involvement affects 5–10% of patients [11], affecting males more commonly, frequently develops late [37], is rarely the presenting feature [38] and is associated with significant morbidity and mortality.

Most commonly, a vascular-inflammatory disease with focal or multi-focal parenchymal involvement is seen, often involving the brainstem. Patients develop acute or subacute brainstem syndromes, hemiparesis and less frequently with other focal signs [39]. A relapsing–remitting course may be followed by a secondary progressive phase, and occasionally a primary progressive course is seen [40]. Histologically, perivascular cuffing with T cells and monocytes with apoptosis of neurones are seen [41]. Cerebral sinus thrombosis and intracranial hypertension also occur, with a better neurological prognosis. Cerebral sinus thrombosis is seen rarely in patients with parenchymal disease, suggesting that different mechanisms underlie both manifestations [39]. In parenchymal disease, cerebrospinal fluid (CSF) shows a pleocytosis and/or raised protein in 60% of patients. In cerebral sinus thrombosis CSF pressure is elevated, but is otherwise normal. Aseptic meningitis may occur. Clinically silent neurological involvement is well recognized [42].

Headache is common, but related to neuroBehçets or uveitis in only 10% of patients. Migraine is significantly more common than in controls, with tension headaches also common [43]. Clinically apparent peripheral nerve involvement is rare [39]; however, clinically silent electrophysiological evidence of neuropathy has been reported [44].

Gastrointestinal disease

Gastrointestinal (GI) involvement affects between 2% and 30% of patients [11,38,45], can occur as a late disease complication [45] and presents typically with anorexia, pain, diarrhoea, perforation or bleeding. Transmural inflammation may give rise to fistulae. The ileocaecal region is affected frequently, but any part of the gastrointestinal tract may be involved. Distinguishing BD from inflammatory bowel disease may prove challenging [46]. Ulcers are identical histologically to ulcerative colitis; if present, granulomata suggest Crohn's disease. Pathergy, when positive, points to a diagnosis of BD.

Vascular disease

Most clinical manifestations of BD result from small vessel vasculitis. Major vessel disease involves predominantly veins, but also affects arteries (usually in the presence of venous disease), affects 8–38% of patients and can be a late complication [37]. Superficial thrombophlebitis and deep vein thrombosis are frequent, usually within 5 years of disease onset, and occasionally as presenting features [47]. Thrombosis of the superior and inferior vena cava, Budd–Chiari syndrome and dural sinus thrombosis are less frequent. Arterial involvement is seen 12% of patients, predisposes to arterial obstruction or aneurysm formation and commonly affects the pulmonary, femoral, popliteal, subclavian and carotid arteries [48]. Pulmonary aneurysm is an important cause of mortality, usually presenting with haemoptysis [37]. Detection of a pulmonary aneurysm (Fig. 3) in the setting of a vasculitic illness is highly suggestive of BD, and is found rarely in other forms of vasculitis [49–51].

Figure 3.

Pulmonary artery aneurysms in Behçet's disease. (a) Chest X-ray with multiple pulmonary masses. (b) Computed tomography chest scan confirming pulmonary artery aneurysms. (c) Right pulmonary artery angiography demonstrating an upper lobe pulomonary artery aneurysm and selective segmental pulmonary artery angiography showing the pulmonary artery aneurysm (the images were kindly provided by Dr Andrew Gordon Consultant Radiologist and Dr Julian Nash, Consultant Rheumatologist, University Hospital of Wales, Cardiff, Wales).

Renal disease

Renal abnormalities are reported in 1–29% [52]; however, studies reporting an incidence > 2% included isolated microalbuminuria. Of 94 patients reported with renal disease, 30% presented with oedema/nephrotic syndrome, with two-thirds detected on urinalysis or biochemical screening [52]. Amyloidosis is the most common cause, associated possibly with expression of serum amyloid A1 alpha/alpha alleles [53]. Amyloidosis was found to affect 14/4000 patients, and was associated with a 50% mortality at 3·5 years [54]. Glomerulonephritis of many types has been reported and renal vascular disease affecting arterial vessels preferentially. Tubular interstitial nephritis is rare; however, the relationship of the tubulointerstitial nephritis–uveitis syndrome remains to be clarified [55]. Cyclosporin nephrotoxicity is an important cause of renal failure in patients with BD [56].

Other manifestations

Joint symptoms (both arthralgia and arthritis) are common, affecting two-thirds of patients [11]. Typically, arthritis is oligoarticular, frequently involving knees, ankles and wrists, is usually non-deforming, with attacks usually lasting less than 2 months. Spinal involvement is rare [57].

Fatigue and malaise may be prominent symptoms, and may be out of proportion to the level of acute-phase reactants. Fevers occur occasionally, but presentation as pyrexia of unknown origin is rare [58]. Weight loss is rarely problematic in the absence of severe stomatitis or GI disease.

As with many systemic vasculitic illness, BD can cause symptoms in virtually any organ system, in addition to the common features outlined above.

Prognosis

The BD is associated with increased mortality [59], mainly because of CNS, pulmonary and large vessel involvement, and bowel perforation and gastrointestinal haemorrhage. A 9·8% mortality over 20 years has been reported [37]. The standardized mortality ratio is highest early after diagnosis and decreases over time. Visual prognosis has improved significantly in patients presenting in the 1990s compared with earlier decades [28]. Disease activity of mucocutaneous and ocular manifestations also decreases with time, and frequently burns out [37].

Management

No curative treatment is available. The goals of treatment in BD are to prevent irreversible organ damage, much of which occurs early in the course of disease, and to prevent and alleviate exacerbations of mucocutaneous, joint and constitutional symptoms that impair patients' quality of life. There is limited evidence from good-quality randomized, controlled trials of sufficient size and duration to guide therapeutic decisions. Recent European League Against Rheumatism recommendations for the management of BD [60] and recent therapeutic reviews provide detailed summaries and recommendations [61–63].

Mucocutaneous disease is treated usually with topical agents, particularly topical steroids. However, when attacks are frequent or severe, systemic therapy with colchicine, pentoxyphylline and dapsone is often useful. In refractory cases thalidomide, azathioprine, tumour necrosis factor (TNF)-α antagonists and interferon-α may be necessary (Table 3). Colchicine is particularly useful for joint disease and erythema nodosum-like lesions [60]. Agents recommended for common presentations of systemic disease are summarized in Table 4. Although used commonly in other systemic vasculitides, there are few data concerning the use of mycophenylate in BD. A single open study found no benefit in mucocutaneous disease [64]; however, beneficial effects have been reported in case reports [65] and in patients with BD included in larger studies of uveitis [66]. Given its similar mode of action to azathioprine, and its enhanced safety profile, mycophenylate merits further evaluation in BD. A small number of patients with refractory disease have undergone autologous [67–69] or allogeneic [69] haemopoietic stem cell transplantation (HSCT), resulting in partial or complete remission. With improving outcomes and lower toxicity conditioning regimens, the risk : benefit ratio of HSCT may be reasonable in patients with refractory neurological [67] or pulmonary disease [68].

Table 3.  Summary of agents used commonly to treat mucocutaneous disease.
Mild disease – topical treatments
DrugExampleDosageComments
Corticosteroids1% triamcinolone in paste (Adcortyl in Orobase)Apply to ulcers qds until healedOral candidiasis
Very useful for pharyngeal ulcers
Hydrocortisone 2·5 mg (Corlan pellets)  
Becotide inhaler sprayed on ulcer base  
Topical anaesthetics0·15% benzyldamine oral rinse or spray (Difflam)Apply every 1·5–3 h, up to 7 daysDilute if stings Occasionally hypersensitivity
Lignocaine gel or sprayApply prnSensitization
Aspiration if sprayed on throat
Anti-microbial mouthwashes0·2% chlorhexidineqds until ulcers healedStaining of teeth
Tetracycline 250 mg, dissolved in waterHold in mouth for 2–3 min, tds for 3 daysFungal infection
Avoid in children, pregnancy and breast-feeding
SucralfateSucralfate suspension 1 g/5 ml5 ml as oral rinse nocte plus apply to ulcers qdsWell-tolerated – no adverse effects noted in RCT
Moderate disease – systemic therapy
Pentoxyifylline400 mg tdsHeadaches
Colchicine0·5 mg tdsGI toxicity
Dapsone100 mg/dayHaemolysis, check G6PD
Thalidomide50–200 mg dailySedation, teratogenicity, neuropathy
Corticosteroids30–60 mg for 1 week, then taperHypertension, hyperglycaemia, etc.
  1. GI, gastrointestinal; RCT, randomized controlled trial; s.c., subcutaneous; TB, tuberculosis; TNF, tumour necrosis factor.

Refractory disease – systemic therapy
Azathioprine1–2·5 mg/kgMonitor for haematological and liver toxicity
Nausea
Interferon-α-2a6 MIU three times per weekMild leucopenia, flu-like symptoms, depression
Anti-TNF-αInfliximab 5 mg/kg or Etanercept 25 mg s.c. twice weekly up to 2 yearsScreen for latent TB. Hold during intercurrent infection
Table 4.  Summary of agents included in the European League Against Rheumatism recommendations for management of systemic manifestations in Behçet's disease [60].
Disease manifestationTreatmentReferences
  • *

    Infliximab 5 mg/kg at weeks 0, 2, 4 and then every 6–8 weeks for up to 2 years [60]; i.v., intravenous.

Eye involvementAzathioprine 2·5 mg/kg/day
Local and systemic steroids
[95,96]
Severe eye diseaseCyclosporin 2–5 mg/kg/day plus Azathioprine and steroids or
interferon-α-2a plus steroids or Infliximab*
[97–99]
[100,101]
Reviewed in [61]
Major vessel disease: venousCorticosteroids
Azathioprine 2·5 mg/kg/day
Cyclosporin 2–5 mg/kg/day
Cyclophosphamide

[96]
[102]
Major vessel disease: arterialSurgical repair for peripheral aneurysms (not pulmonary)
Corticosteroids
Cyclophosphamide for 2 years

[103,104]
Neurological diseaseAvoid cyclosporin (neurotoxicity)
Methylprednisolone 1 g/day × 3–7 plus oral steroids × 2–3 months
Methotrexate
Azathioprine 2·5 mg/kg/day
Cyclophosphamide i.v. monthly
Interferon-α
Infliximab*

[60]
[105,106]
[60]
[60]
[107]
Reviewed in [61]
Gastrointestinal diseaseSulfasalazine
Corticosteroids
Azathioprine 2·5 mg/kg/day
Infliximab
Thalidomide


[108,109]
Reviewed in [61]
[110]

Epidemiology, aetiology and pathogenesis

The BD is prevalent along the Silk Road, an ancient trading route between the Mediterranean and East Asia. The prevalence is highest in Turkey (420/100 000) [70], between 13·5 and 20/100 000 in the Middle East and Asia and <1/100 000 in the United Kingdom and United States [11]. A positive family history is reported in up to 11·3% of cases [45], more commonly in paediatric than adult cases [71,72]. An autosomal recessive mode of inheritance has been proposed in paediatric BD, but not in adult disease, suggesting genetic heterogeneity [72]. No systematic twin studies have been reported, and of five pairs of monozygotic twins reported, three are concordant for the disease [73–76].

There is a strong association with HLA-B*5101, demonstrated in several different ethnic groups; however, only 60% of patients with BD express HLA-B*5101, and this HLA allele is seen frequently in the absence of disease. Polymorphisms of associated genes in linkage disequilibrium with HLA-B*5101 have been investigated for a possible independent association, including major histocompatibility complex class I chain-related gene A [77] and TNF-α[78]. However, HLA-B*5101 is now accepted to be the major disease susceptibility gene, contributing approximately 20% of the genetic risk [79], but additional immune effects may be elicited by linked genes [80]. A genetic association study has identified 16 loci of interest [81]. Both constitutional and somatic trisomy 8 have been associated with myelodysplastic syndromes, complicated with BD [82], suggesting that gene dosage, not merely polymorphism, may be relevant in this complex disease.

The most widely accepted theory for the pathogenesis of BD is that an environmental stimulus elicits an abnormal immune response in a genetically susceptible host. A variety of putative inciting antigens have been proposed (reviewed in [12]). Interestingly, HLA-B51 binds a large pool of peptides with low affinity, which may lead to inefficient tolerance-induction [83]. An infection or inflammatory event may result in the presentation of generally cryptic antigens to the immune system. The ensuing immune response is dysregulated with excessive cytokine production (including TNF-α) and an unusual pattern of T cell activation [84]. Endothelium is activated with elevated soluble intercellular adhesion molecule-1 detected in serum in the majority of patients with ocular disease [85]. Although most offspring are healthy [86], cases of neonatal BD have been described, with resolution by 8 weeks [87–91]. This suggests that a soluble factor capable of transplacental passage such as maternal antibody may be implicated. A variety of autoantibodies have been described in BD; however, few have sufficient specificity to play a pathogenic role. Recent studies using proteomic approaches [92] and screening of endothelial expression libraries have identified novel autoantibodies [92,93,94], some of which induce functional effects on cultured endothelial cells [92,93]. It is hoped that such approaches may yield a much-needed diagnostic test, as well as better understanding of this enigmatic condition in the near future.

Ancillary