Pathophysiology: The cause of Behcet disease is not known; however immunogenetics, immune regulation, vascular abnormalities, or bacterial and viral infection may have a role in its development.
Frequency:
· In the US: Behcet disease is not common in the US with an incidence of 5 cases per 100,000 people.
· Internationally: Behcet disease is most prevalent (and more virulent) in the Mediterranean, Middle East, and Far East with an estimated 1 in 10,000 people affected.
Mortality/Morbidity:
· Chronic morbidity is usual; the leading cause is ophthalmic involvement, which can result in blindness. The effects of the disease may be cumulative, especially with neurologic, vascular, and ocular involvement.
· Mortality is low but can occur from neurologic involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy.
Sex: Men are affected more often, and with more severe disease, than women in some Mediterranean areas. In Iran, for example, the male-to-female ratio was 24:1 among 1712 patients. In Turkey, the ratio was 16:1 among 427 patients.
Age: Onset can occur at any age, but is most common during the third decade of life.
History: Signs and symptoms, which may be recurrent, may precede the onset of the mucosal membrane ulcerations by 6 months to 5 years.
· Prior to the onset of BD, patients may experience a variety of symptoms.
o Malaise
o Anorexia
o Weight loss
o Generalized weakness
o Headache
o Perspiration
o Decreased or elevated temperature
o Lymphadenopathy
o Pain of the substernal and temporal regions
· A history of (1) repeated sore throats, (2) tonsillitis, (3) myalgias, and (4) migratory erythralgias without overt arthritis is common.
· Oral ulcers are the most common and earliest sign of Behcet disease.
· Diagnosis of Behcet disease is based on clinical criteria because of the absence of a pathognomonic laboratory test. The period between the appearance of an initial symptom and a major or minor second manifestation can be up to a decade long in many cases.
· The number of different criteria/classification systems that have been introduced over the past 25 years reflects the failure of any single one to meet clinical demands. The revised 1987 criteria of the Japanese group (Shimizu) have been widely applied (see Table 1).
· More recently, the diagnostic criteria of the International Study Group for Behcet Disease (ISGBD) have been applied in establishing firmer diagnoses (see Table 2).
· The major limitation of these criteria, however, lies in the fact that recurrent oral ulceration is the linchpin for diagnosis of Behcet disease. For example, patients with uveitis and genital ulcers, without oral aphthosis, would not be considered to have Behcet disease, although this is in fact a far-advanced form of the disease.
· Therefore, we recommend that the Japanese criteria be applied concurrently with the ISGBD criteria until a more exact system is devised.
Physical:
· Oral ulcers
o Oral aphthae that occur in patients with Behcet disease are indistinguishable from common aphthae (canker sores).
o Aphthae may be more extensive, more painful, may occur more frequently and evolve quickly from a pinpoint flat ulcer to a large sore.
o Lesions are usually shallow or deep (2-30 mm in diameter) with a central, yellowish, necrotic base and a punched-out, clean margin.
o They can appear singly or in crops, are located anywhere in the oral cavity, persist for 1-2 weeks, and subside without leaving scars.
o Most common sites are the tongue, lips, buccal mucosa, and gingiva; tonsil, palate, and pharynx are less common.
o Interval between recurrences ranges from weeks to months.
· Oral ulcers can be classified into 3 types:
1. Minor ulcer: 1-5 small, moderately painful ulcers persisting for 4-14 days (see Picture 1)
2. Major ulcer: 1-10 very painful ulcers, measuring 10-30 mm in size persisting up to 6 weeks that can leave a scar on healing (see Picture 2)
3. Herpetiform ulcer: Recurrent crops of as many as 1000 small and painful ulcers (see Picture 3)
· Genital manifestations
o Genital ulcers resemble their oral counterparts but may show greater scarring. They have been found in 56.7-97% of cases, but their appearance mostly is as a secondary symptom accompanying oral ulcers.
o In males, the ulcers usually occur on the scrotum (see Picture 4), penis, and groin.
o In females, they occur on the vulva (see Picture 5), vagina, groin, and cervix.
o Ulcers also have been found in the urethral orifice and perianal area.
o Epididymitis may arise and is a minor diagnostic criterion for the disease according to the Behcet Disease Research Committee of Japan.
o An additional genital symptom is orchiepididymitis, seen in 10.8% of men.
· Cutaneous manifestations
o A variety of skin lesions have appeared in patients with Behcet disease (58.6-97%) including (1) erythema nodosum-like lesions (most frequent) (see Picture 6), (2) papulopustular eruptions (see Picture 7), (3) erythema multiforme-like lesions, (4) thrombophlebitis, (5) ulcers, (6) lesions resembling Sweet syndrome (see Picture 8), (7) bullous necrotizing vasculitis, and (8) pyoderma gangrenosum.
o Nonspecific skin inflammatory reactivity to any scratches or intradermal saline injection is a common and specific manifestation of these lesions (pathergy) (see Picture 9).
o Lesions often occur in combination (eg, erythema nodosumlike lesions and papulopustular eruptions).
o Follicle-based pustules or acne lesions are not considered specific lesions of Behcet disease.
· Ocular manifestations
o Ocular involvement is the major cause of morbidity and the most dreaded complication, as it occasionally progresses rapidly to blindness. It is reported in 47-65% of patients with BD.
o The most diagnostically relevant lesion is posterior uveitis (retinal vasculitis) (see Picture 10). Other lesions include anterior uveitis, iridocyclitis, chorioretinitis, scleritis, keratitis, vitreous hemorrhage, optic neuritis, conjunctivitis, retinal vein occlusion, and retinal neovascularization. Hypopyon, which is considered the hallmark of BD, is now uncommon.
o Eye disease usually is present from the outset but also may develop within the first few years. Decreased visual acuity is a result of secondary glaucoma, cataracts, or vitreous hemorrhage. Blindness has been reported to occur within 4-5 years from the onset of ocular symptoms. Retinal vein thrombosis leading to sudden blindness is not rare.
· Vascular involvement (7-29% of patients; mostly men)
o Histologic findings include thickening of media, splitting of the elastic fibers, and perivascular round cell infiltration.
o The 4 types of vascular lesions recognized in Behcet disease are (1,2) arterial and venous occlusions, (3) aneurysms, and (4) varices.
o Venous involvement usually is limited to occlusion, with the varices rarely affected.
o Affected sites of the venous system are the superior vena cava, inferior vena cava, deep femoral vein, and subclavian vein.
o Arterial complications account for 7% of cases (aneurysm and occlusion are most common).
o The subclavian artery and pulmonary artery are most common arteries occluded. Depending on the site, arterial occlusions can have different clinical presentations. Pulseless disease is due to subclavian artery occlusion.
o Hypertension can originate from renal artery stenosis.
o Femoral artery stenosis and intermittent claudication cause avascular necrosis of the femoral head.
o Pulmonary vasculitis can produce dyspnea, chest pain, cough, or hemoptysis.
o Aneurysm formation accounts for most vascular deaths.
o Common sites of aneurysms are abdominal aorta, femoral artery, and thoracic artery.
o As vascular involvement of BD can be significant and prove life-threatening, it is vital to diagnose and treat vascular involvement early.
· Gastrointestinal involvement
o The clinical spectrum of gastrointestinal effects is enormously varied and occurs in over 10% of patients with BD.
o Gastrointestinal involvement was reported in 42 out of 410 patients (10.2%).
o Anorexia, vomiting, dyspepsia, diarrhea, abdominal distention, and abdominal pain all may occur.
· Joint manifestations.
o More than one half of the patients develop signs or symptoms of synovitis, arthritis and/or arthralgia during the course of the disease.
o The most frequent minor feature in childhood-onset BD was arthritis, occurring in 11 of 40 patients.
o The involvement of multiple joints is common.
o Clinical features were pain (57 cases), tenderness (52 cases), swelling (48 cases), limitation of joint movement (26 cases), warmth (11 cases), and morning stiffness (10 cases).
· Neurologic manifestations
o The incidence of neurologic involvement in BD varies from 3.2-49% according to the reports of different populations.
o Neurologic involvement may present (in various combinations) as meningoencephalitis, a multiple sclerosis-like illness, acute myelitis, stroke or pseudotumor cerebri.
o Three categories of neurologic involvement are (1) brain stem syndrome, (2) meningomyelitis syndrome, and (3) organic confusional syndrome.
o Neurologic involvement is one of the most serious complications, leading to severe disability and a high fatality rate. Neurologic manifestations usually occur within 5 years of onset.
o Severe headache is the most frequent initial neurological symptom.
· Pregnancy-associated manifestations
o Pregnant women with BD may experience more severe symptoms during the course of the pregnancy, especially in the first trimester.
o Close follow-up is necessary to monitor health of mother and baby.
· Other organ manifestations
o Myocarditis and cardiac vessel disease may occur.
o Major hemoptysis may result from pulmonary vascular thrombosis, aneurysms, or vasculitis.
o Cases with renal involvement, such as mild asymptomatic glomerulonephritis, also have been reported. However, most patients were asymptomatic.
· Pathergy (skin hyperreactivity)
o The pathergy phenomenon is considered an outstanding feature of BD.
o Following a needle prick or intradermal injection with saline or dilute histamine, the puncture site becomes inflamed and develops a small sterile pustule due to hyperactivity of the skin to any intracutaneous insult.
o The pustular reaction of the skin is thought to denote increased neutrophil chemotaxis.
o The presence of pathergy strongly suggests the diagnosis of BD.
o Higher positivity (84-98%) is found in Mediterranean and Middle Eastern countries as compared to Far Eastern countries (40-70%), with Western countries having significantly lower positivity than either region.
Causes:
· Immunogenetics
o HLA-B51 or its B101 allele is significantly associated with BD in Japan, Korea, Turkey, and France, as well as with the ocular manifestations in Britain. Although HLA-B51 transgenic mice failed to develop any manifestation of BD, their neutrophils showed excessive function.
o MICA allele is a polymorphic MHC class I related gene A (MICA) family. MICA6 allele has recently been shown to be significantly associated with BD (74%), compared with controls (45.6%) in Japan. The relationship between MICA6 and BeD was confirmed in France. MICA6 allele is thought to be in linkage disequilibrium with HLA-B51, so the search for genes related to BD continues.
· Viral and bacterial infection
o Investigations of the etiology of BD have focused predominantly on (a) herpes simplex virus infection, (b) streptococcal infection and (c) autoimmunity or cross-reactivity between microbial and oral mucosal antigens.
o Behcet suggested the herpes simplex virus as a causative agent in his first report. The new method called polymerase chain reaction (PCR) improved remarkably the diagnostic significance of viral infections, especially herpes simplex virus (HSV). HSV DNA was detected in saliva, genital ulcer, and intestinal ulcers of patients with BD. Behcet diseaselike symptoms were induced in an ICR mouse after inoculation of HSV into the earlobe.
o Acquired hypersensitivity to streptococcal antigens plays an important role in the etiopathology of BD.
o The multiplicity of etiologic factors may have a common denominator in the 65kD microbial HSP, which shows significant homology with the human 60kD mitochondrial HSP. Indeed, the uncommon serotypes of Streptococcus sanguis found in BD cross-react with the 65kD HSP, which also shares antigenicity with an oral mucosal antigen.
o T-cell epitope mapping has identified 4 peptides derived from the sequence of the 65kD HSP that stimulate specifically TCR+ lymphocytes from patients with Behcet disease. These peptides (111-125, 154-172, 219-233, and 311-325) show significant homology with the corresponding peptides (136-150, 179-197, 244-258, 336-351) derived from the human 60kD HSP. B-cell epitopes within mycobacterial HSP65 or human HSP60 overlapped with the T-cell epitopes and both IgG and IgA antibodies were identified. Among the 4 T and B cell epitopes, peptide 336-351 of the 60kD HSP is significantly associated with Behcet disease in Britain, Japan and Turkey. HSP60/65 was also found to be significantly increased in the epidermal cells of skin lesions in Behcet disease, and antibodies to HSP65 were significantly raised in the cerebrospinal fluid from patients with neurological manifestations of Behcet disease. An experimental model of Behcet disease uveitis was established in rats, in which subcutaneous immunization with peptide
336-351 and adjuvants elicited uveitis in about 80% of Lewis rats. Furthermore, a mucosal model of induction of uveitis was developed in rats by oral or nasal administration of peptide 336-351 without an adjuvant, and this is consistent with the oral onset of ulceration in more than 90% of patients with Behcet disease.
· Immunological abnormalities
o In Behcet disease the TH-1 cytokine IFN is raised in serum, in T cells of skin and CSF and IL-12 is generated by stimulation of CD4+ T cells with the HSP peptide 336-351, though IL-12 can also be secreted by neutrophils in Behcet disease. However, the concentration of the TH-2 cytokine IL-6 also is increased in the serum of patients with Behcet disease, especially in the active stage, as was also found with IL-10 on stimulation of peripheral blood mononuclear cell (PBMC).
o Stimulation with S sanguis (KTH-1) of T-cell lines generated from patients with Behcet disease suggests that TH-1 type mRNA is induced (IL-2 and IFN).
o Investigations of intracellular IFN and IL-4 suggest that there is a polarization toward the TH-1 type of cells in patients with active Behcet disease, because of a significant increase in the intracellular IFN that was not observed with IL-4. However, the converse was found in another investigation by stimulating PBMC, with increased TH-2 cytokines (IL-10 and decreased IL-2 or IFN) in active Behcet disease.
o The adhesion molecule ICAM-1 was enhanced in human dermal microvascular endothelial cells after treatment with serum from patients with Behcet disease and this may have induced increased adhesion of T cells to the endothelial cells.
o Proinflammatory cytokines TNF, IL-1, and IL-8 are raised in serum with Behcet disease are also unregulated in PBMC and neutrophils of patients with Behcet disease.
· Endothelial and vascular dysfunctions
o Vascular changes leading to vasculitis and thrombosis are one of important pathological features of Behcet disease.
o Antiendothelial cell antibodies are detected in diseases with immune-mediated vascular damage and show significantly increased prevalence in Behcet disease.
o T cells (mostly CD4 cells), B cells, and neutrophils are infiltrated perivascularly.
o Prostanoid synthesis in endothelial cells or vessel walls is impaired, whereas von Willebrand factor, thromboxane and thrombomodulin are increased.
o The level of endothelin (ET)-1,2 is increased in patients with vascular involvement of Behcet disease.
o Endothelial cell dependent vasodilator function is significantly impaired in patients with Behcet disease and is demonstrated by high-resolution ultrasound imaging.
Lab Studies:
· Behcet disease cannot be confirmed through clinical laboratory results.
o Mild anemia and leukocytosis are observed in some patients with chronic disease.
o Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and other acute phase reactants may be elevated during the active stage of Behcet disease, but they do not correlate well with the clinical activity.
o Increase of alpha 2-globulins is often seen. Serum immunoglobulins, especially IgA, may be elevated.
o Circulating immune complexes often are present.
o Rheumatoid factors (RF) and antinuclear antibodies (ANA) are absent.
o Antineutrophil cytoplasmic antibodies (ANCA) and antiphospholipid antibodies are usually negative.
Histologic Findings: Etiology and pathogenesis of Behcet disease remain obscure, although many reviews describe a lymphocytic vasculitis.
Vasculitis is said to affect vessels of all sizes; the various skin lesions are thought to be secondary to a small vessel vasculitis.
T-cell subsets with a preponderance of helper-inducer cells over T suppressor-cytotoxic cells were observed in lesions.
Electron Microscopic Observations
Examination of erythema nodosum-like lesions will show microvascular changes and lymphocyte-mediated fat cell lysis. Additionally, small dermal blood vessels embolized by thrombus are observed at the sites of needle prick reaction as well as erythema nodosum-like lesions.
The early changes in fat cells may be caused by vascular changes brought about by the specific degeneration of endothelial cells and vascular stenosis associated with the delayed-type hypersensitivity reaction.
Medical Care: Although multiple therapeutic modalities have been employed, treatment is far from satisfactory. Treatment of Behcet disease seems to be symptomatic and empiric. Therapeutic efficacy has been difficult to evaluate due to the variable course of the disease and the limited number of cases for clinical investigation.
· Local therapy
o Tetracycline remains the drug of choice for aphthous stomatitis and oral ulcers of Behcet disease.
o The patient should dissolve the contents of a 250-mg tetracycline capsule in 5 mL of water or flavored syrup and hold the solution in the mouth for about 2 minutes before swallowing. Repeat 4 times daily.
o Topical corticosteroids are effective for oral or genital ulceration if they are applied during the prodromal stage of ulceration.
o Other useful drugs include Lidocaine gel (2%), sucralfate suspension, and 5% Amlexanox.
· Systemic therapy--There is no single effective drug.
o Corticosteroids are the mainstay of treatment for all the various clinical manifestations. Although they have a beneficial effect on acute manifestations, there is no definite evidence that they are effective in controlling progression.
o The steroid side effects that can result from long-term use must be considered.
o Mucocutaneous lesions and arthritis have been treated with nonsteroidal antiinflammatory drugs, zinc sulfate, levamisole, colchicine, dapsone, or sulfapyridine and thalidomide (use is strictly limited because of its teratogenicity). Immunosuppressive therapy with azathioprine, chlorambucil, or cyclophosphamide has been used.
o Uveitis and central nervous system involvement is treated with systemic corticosteroids, azathioprine, or cyclosporine.
o Anticoagulants are given to patients with thromboses.
o Recent therapeutic approaches have included cyclosporine, thalidomide, interferon alfa, interferon gamma, acyclovir, high-dose corticosteroids or cyclophosphamide pulse therapy and FK506 (an immunosuppressive agent similar to cyclosporine).
o FK506 has been particularly noteworthy. The Japanese FK506 study group reported that FK506 was effective in treating refractory uveitis in a dosage-dependent manner. Side effects were renal impairment (28.3%), neurologic symptoms (20.8%), gastrointestinal symptoms (18.9%), and hyperglycemia (13.2%). The study group also noted the need for further clinical investigations on FK506 before more widespread application.
Surgical Care: Surgical therapy becomes necessary in serious conditions including the following:
o Gastrointestinal perforation
o Enterocutaneous fistula formations
o Spontaneous arterial aneurysm formation
o Thrombotic obstruction in large caliber vessels
o Cardiac involvement
· Proper timing for surgical treatment is important.
· Delayed wound healing or inflammation at operative sites may be related to pathergy.
Consultations:
· Dermatology - for evaluation of mucocutaneous lesions (ie, oral ulcer, genital ulcer, skin lesions)
· Ophthalmology - for evaluation of eye involvement
· Rheumatology, orthopedic surgery - for evaluation of joint involvement
· Neurology, psychiatry - for evaluation of CNS involvement
· Internal Medicine - for evaluation of gastrointestinal, pulmonary, renal, or endocrine involvement
· General Surgery - for evaluation of gastrointestinal involvement
· Chest Surgery, cardiology - for evaluation of cardiovascular involvement
· ENT, dental clinic - for evaluation of oral cavity