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‫بسم هللا الرحمن الرحيم‬
‫وفوق كل ذي علم عليم‬
‫صدق هللا العظيم‬
New EvidenceBased Treatment
Approach in
BEHCET’S DISEASE
Behcet’s Disease (BD)
Is a chronic, relapsing, and debilitating
systemic vasculitis of unknown etiology
with the clinical features of mucocutaneous
lesions, ocular, vascular, articular,
neurologic, gastrointestinal, urogenital, and
pulmonary involvement.
Hulusi Behcet (1937) described the classical
signs of the disease.
Epidemiology:
Recent epidemiologic surveys show the following:
. Age: 3rd – 4th decade
. Sex distribution is roughly equal, in Iraq (4 male : 1 female)
. HLA (B51 & B52),
Iraq B51 (55%), DR2, DO3 in families, family Hx (10%)
. The prevalence:
14-20 per 100000 along the ancient Silk Road populations,
(Italy, Turkey, KSA, Iran, China, Korea, Japan).
Iraq (17 per 100000)
InTurkey it is found to be nearly 1/250 of the population
aged 12 or older, whereas in England is < 1/100000.
Diagnosis:
It is based on clinical criteria, as there is no pathognomonic
test.
Mucocutaneous lesions figure may be considered the
hallmarks of BD & often precede other manifestations.
Therefore, their recognition may permit earlier diagnosis
and treatment, with salutary results.
Oral ulcers, genital ulcers, and cutaneous lesions together
with ocular lesions and arthropathy are the most frequent
features of the disease in all countries.
Table 1 International study group criteria for Behçet’s disease in 1990
Finding
Definition
Recurrent oral
ulceration
Minor aphthous, major aphthous, or herpetiform ulcers observed
by the physician or patient, which have recurred at least three times
over a 12-month period
Recurrent
genital ulceration
Aphthous ulceration or scarring observed by the physician or patient
Eye lesions
Anterior uveitis, posterior uveitis, or cells in the vitreous on slit-lamp
examination; or retinal vasculitis detected by an ophthalmologist
Skin lesions
Erythema nodosum observed by the physician or patient,
pseudofolliculitis, or papulopustular lesions; or acneiform nodules
observed by the physician in a post-adolescent patient who is not
receiving corticosteroids
Positive pathergy
test
Test interpreted as positive by the physician at 24 to 48 hours
TABLE 2 Revised Diagnostic Criteria Proposed by the Behcet’s
Disease (BD) Research Committee of Japan in 2003
Main points:
Main symptoms:
Recurrent aphtous ulcers on oral mucosa
Skin lesions (EN, subcutaneous thrombophlebitis, follicular papules, acneform papules, skin hypersensitivity)
Ocular lesions (anterior and/or posterior uveitis)
Genital ulcers
Additional symptoms:
Arthritis without deformity or sclerosis
Epididymitis
Gastrointestinal lesion (Ileocecal ulceration)
Vascular lesions
Central nervous system lesions
Table 2 cont.
Criteria for diagnosis of disease types:
Complete type (4 main symptoms)
Incomplete type (3 of main symptoms, or 2 of main symptoms & 2 additional symptoms;; Typical
ocular lesion and another main symptom, or two additional symptoms)
BD suspected (Some main symptoms appear, but the case does not meet the criteria for the
incomplete type
Typical additional symptom is recurrent or becomes more severe)
Special lesions (GIT lesions, Vascular lesions, Neuronal lesions)
Laboratory data
Negative or positive pathergy test
Negative or positive prick test for vaccine for streptococci
Inflammatory responses (increase of ESR, C-reactive protein +ve, neutrophilia, increase in complement
activity)
Positive for HLA-B51
Pathological findings
Treatment:
Although several effective treatments currently exist, none of
them result in a cure of the disease and some are associated
with significant side effects.
Choice of Rx based on clinical presentation , site affected.
Main aim of Rx should be the prevention of irreversible organ
damage, especially, during the early, active phase of the
disease.
Close monitoring and appropriate treatment may control and
change the course of the disease.
It is wise to remember that especially male patients and those
with early onset disease are associated with more severe
presentations including major vessel disease, ocular, GIT, and
CNS involvement and, therefore, require more aggressive
treatment.
Aim:
This paper overviews the current state of knowledge
regarding the therapeutic approaches for BD. Based
on the mainly controlled studies, personal experience
in clinical practice and basic research in this field.
A stepwise, symptom-based, evidence-based algorithmic
approach for the management of BD was proposed.
This approach might enable clinicians to rationalize and
further increase the selection of the most appropriate
therapy among numerous treatment options.
Table 3: Activity spectrum of systemic therapeutic agents on Behcet’s disease in
randomized, controlled studies.
Treatment
Dose
Indication &Reference
Corticosteroids versus placebo
40mg methylpr./every
3w
Decrease the frequency of EN in women, (86 pt, Recent
randomized, placebo-controlled study)
Colchicine versus placebo
1mg/d
Decrease in overall disease activity index and significant
improvement in OUs, GUs, PPLs, and EN in both sexes,
(169pt.) (Davatchi et al.)
Colchicine versus Colchicine +
Benzathine penicillin
1mg/d; 1.2MU/mo.
Combined treatment more effective in reducing duration
and frequency of OUs, EN, Gus & arthritis than using each
drug alone, (Calguneri et al), (Al-Waiz et al)
Rebamipide versus placebo
300 mg/d
Reduces the number of OUs and pain 65%, prevent
recurrence, no S/E. (35pt. For 3-6mo.) (Matsuda et al.)
Zinc sulfate versus placebo
300 mg/d
Significant improvement in the clinical manifestations index
of mucocutaneous lesions without any S/E, (32pt.) (Sharquie
et al.)
Dapsone versus placebo
100 mg/d
Effective on the number, healing time and frequency of OUs,
number of GUs, and frequency of EN and PPLs. Suppresses
arthritis and epididymitis, (20pt.) (Sharquie et al.)
Thalidomide versus placebo
100–300 mg/d
Sustained remission of OUs, GUs, and PPLs, (63pt. 30%
remission over 6 mo.)
Azathioprine versus placebo
2,5 mg/kg/d
Reduces the occurrence of OUs, GUs, arthritis, and ocular
symptoms. Prevents the development of new eye disease, (73pt.)
Cyclophosphamide +
Corticosteroids
versus Corticosteroids
1 g/m2/mo
Combined treatment of CCP and corticosteroids more effective
in eye disease than corticosteroids alone
Cyclosporin A versus Colchicine
10 mg/kg/d
CyA more effective on the severity and frequency of OUs, GUs,
and PPLs. Superior to colchicine in decreasing the frequency
and severity of ocular attacks,
Cyclosporin A versus conventional
treatments (prednisolon, chlorambucil),
or Cyclosporin A versus
Cyclophosphamide
10 mg/kg/d
CsA more effective than conventional therapy in ocular disease,
however, conventional therapy superior to CyA in controlling
OUs, GUs, and arthritis. Improvement of hearing loss in 25% of
patients receiving CyA treatment, (BenEzra et al.), (Elidan et l.)
Interferon-α versus placebo
6 MU/d-3 x/w
5mg/kg/d
3 MU/d for 2wk.
3 MU/3x/wk. for 2yr
Effective on pain and healing time of OUs and frequency of GUs
and PPLs. Also helpful in decreasing frequency and duration of
EN, TFB, and articular symptoms, (Hamuryudan et al. 48wk.),
(Kotter et al. 50pt.), (Tugal-Tutkan et al. 44pt.)
(Onal et al.) 37pt. To refractory panuveitis response 95%, com.
remission 76% by 3mo.
S/E (flulike illness, n.&v., liver enz., psych. s/e & depression)
(Sfikakis et al., Ohno et al., Tugal-Tutkan et al) effect on eye,
mucocut. GIT, CNS.
Anti TNF-a (infliximab, adalimumab,
etanercept)
Etanercept versus placebo
25mg twice/wk for
4wk
Reduces the occurrence of OUs, nodular skin lesions, and PPLs,
(Melikoglo et al.) 40 male.
Rituximab versus cytotoxic
combination therapy
2 1000-mg courses
(15-day interval)
A significant improvement in total adjusted disease activity
index in rituximab group, (Davatchi et al.) 20pt. Over 6 mo.
Table 3 cont.
Others: MTX
Mycophenolate mofetil
Autologous hematopoietic
stem cell tr.
Pentoxifylline
Sulfasalazin
Mucocut., CNS, Ocular
Cytoid macular edema
Severe GIT, pul.,& CNS
SURGICAL treatment
Art. Aneurysms, Bowel perforation, cut.
Fistula, Cardiac, & Glucoma.
Mucocut., Ocular
GIT
Table 4: Summary of evidence-based algorithmic treatment for
mucocutaneous Behcet’s disease.
*since the effect of topical Rx is limited to application site, it should be associated with systemic Rx.
1st line
∗Topical: Antimicrobial agents, Sucralfate, Corticosteroids,
Pimecrolimus
Systemic: Colchicine, Colchicine + Benzathine
penicillin
2nd line
∗Topical: Anti-inflammatory agents, Amlexanox
Systemic: Corticosteroids, Dapsone, Azathioprine,
Thalidomide
3rd line
∗Topical: Anaesthetics, Silver nitrate
Systemic: Zinc sulfate, Rebamipide, Pentoxifylline,
Methotrexate, Cyclosporine-A, IFN-α, Anti-TNF-α
Table 5: Summary of evidence-based algorithmic treatment for
Ocular Behcet’s disease.
*Topical Rx as a sole agent should be restricted to those who has mild uveitis (ant. Uveitis)
1st line
∗Topical: corticosteroids + mydriatics ±
cycloplegic agents
Systemic: Corticosteroids, Cyclosporine-A,
Azathioprine
2nd line
IFN-α, Anti-TNF-α
3rd line
Methotrexate, Mycophenolate mofetil,
Cyclophosphamide, Rituximab
Table 6: Summary of evidence-based algorithmic treatment for
Articular Behcet’s disease.
1st line
Colchicine, Colchicine + Benzathine
penicillin, or anti-inflammatory analgesics
2nd line
Azathioprine, Corticosteroids (syst. Or
intraarticular)
3rd line
Methotrexate, Salazopyrine, IFN-α,
Anti-TNF-α
Table 7: Summary of evidence-based algorithmic treatment for
Vasculo-Behcet’s disease.
1st line
Corticosteroids, Azathioprine,
Cyclophosphamide (monthly pulse dose)
2nd line
Anti-TNF-α
3rd line
Anticoagulation, Antiplatelets, Surgery
Table 8: Summary of evidence-based algorithmic treatment for
Neuro-Behcet’s disease.
1st line
Corticosteroids
2nd line
Azathioprine, cyclophosphamide,
Anti-TNF-α, IFN-α
3rd line
Methotrexate, Anticoagulation
Table 9: Summary of evidence-based algorithmic treatment for
Gastrointestinal-Behcet’s disease.
1st line
Sulfasalazine, corticosteroids
2nd line
Azathioprine
3rd line
Anti-TNF-α
Conclusion:
treatment of BD has become much more
effective in recent years. Due to recent
advances in understanding the pathogenesis
of the underlying disease and availability of
a wide spectrum of therapeutic agents,
alleviation of most symptoms, control of the
disease, and, even, modification of the
course of the disease are now possible.
Thanks for your
listening