1. بسم الله الرحمن الرحيم وفوق كل ذي علم عليم صدق الله العظيم
بسم الله الرحمن الرحيم وفوق كل ذي علم عليم صدق الله العظيم

2. New Evidence-Based Treatment Approach in BEHCET’S DISEASE

3. 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.

4. 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: per along the ancient Silk Road populations, (Italy, Turkey, KSA, Iran, China, Korea, Japan). Iraq (17 per ) InTurkey it is found to be nearly 1/250 of the population aged 12 or older, whereas in England is < 1/ n

5. 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.

6. Table 1 International study group criteria for Behçet’s disease in 1990
Definition
Finding
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 oral ulceration
Aphthous ulceration or scarring observed by the physician or patient
Recurrent genital ulceration
Anterior uveitis, posterior uveitis, or cells in the vitreous on slit-lamp
examination; or retinal vasculitis detected by an ophthalmologist
Eye 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
Skin lesions
Test interpreted as positive by the physician at 24 to 48 hours
Positive pathergy test

7. 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

8. Complete type (4 main symptoms)
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

9. 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.

10. 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.

11. Indication &Reference
Table 3: Activity spectrum of systemic therapeutic agents on Behcet’s disease in randomized, controlled studies.
Indication &Reference
Dose
Treatment
Decrease the frequency of EN in women, (86 pt, Recent randomized, placebo-controlled study)
40mg methylpr./every 3w
Corticosteroids versus placebo
Decrease in overall disease activity index and significant improvement in OUs, GUs, PPLs, and EN in both sexes, (169pt.) (Davatchi et al.)
1mg/d
Colchicine versus placebo
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)
1mg/d; 1.2MU/mo.
Colchicine versus Colchicine +
Benzathine penicillin
Reduces the number of OUs and pain 65%, prevent recurrence, no S/E. (35pt. For 3-6mo.) (Matsuda et al.)
300 mg/d
Rebamipide versus placebo
Significant improvement in the clinical manifestations index of mucocutaneous lesions without any S/E, (32pt.) (Sharquie et al.)
Zinc sulfate versus placebo
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.)
100 mg/d
Dapsone versus placebo
Sustained remission of OUs, GUs, and PPLs, (63pt. 30% remission over 6 mo.)
100–300 mg/d
Thalidomide versus placebo

12. 2,5 mg/kg/d 1 g/m2/mo 10 mg/kg/d 2 1000-mg courses (15-day interval)
Reduces the occurrence of OUs, GUs, arthritis, and ocular
symptoms. Prevents the development of new eye disease, (73pt.)
2,5 mg/kg/d
Azathioprine versus placebo
Combined treatment of CCP and corticosteroids more effective
in eye disease than corticosteroids alone
1 g/m2/mo
Cyclophosphamide + Corticosteroids
versus Corticosteroids
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,
10 mg/kg/d
Cyclosporin A versus Colchicine
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.)
5mg/kg/d
Cyclosporin A versus conventional
treatments (prednisolon, chlorambucil), or Cyclosporin A versus Cyclophosphamide
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)
6 MU/d-3 x/w
3 MU/d for 2wk.
3 MU/3x/wk. for 2yr
Interferon-α versus placebo
(Sfikakis et al., Ohno et al., Tugal-Tutkan et al) effect on eye, mucocut. GIT, CNS.
Reduces the occurrence of OUs, nodular skin lesions, and PPLs, (Melikoglo et al.) 40 male.
25mg twice/wk for 4wk
Anti TNF-a (infliximab, adalimumab, etanercept)
Etanercept versus placebo
A significant improvement in total adjusted disease activity
index in rituximab group, (Davatchi et al.) 20pt. Over 6 mo.
mg courses
(15-day interval)
Rituximab versus cytotoxic combination therapy

13. Table 3 cont.
Mucocut., CNS, Ocular
Cytoid macular edema
Severe GIT, pul.,& CNS
Mucocut., Ocular
GIT
Others: MTX
Mycophenolate mofetil
Autologous hematopoietic
stem cell tr.
Pentoxifylline
Sulfasalazin
Art. Aneurysms, Bowel perforation, cut. Fistula, Cardiac, & Glucoma.
SURGICAL treatment

14. 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.
∗Topical: Antimicrobial agents, Sucralfate, Corticosteroids, Pimecrolimus
Systemic: Colchicine, Colchicine + Benzathine penicillin
1st line
∗Topical: Anti-inflammatory agents, Amlexanox
Systemic: Corticosteroids, Dapsone, Azathioprine, Thalidomide
2nd line
∗Topical: Anaesthetics, Silver nitrate
Systemic: Zinc sulfate, Rebamipide, Pentoxifylline, Methotrexate, Cyclosporine-A, IFN-α, Anti-TNF-α
3rd line

15. 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)
∗Topical: corticosteroids + mydriatics ± cycloplegic agents
Systemic: Corticosteroids, Cyclosporine-A, Azathioprine
1st line
IFN-α, Anti-TNF-α
2nd line
Methotrexate, Mycophenolate mofetil,
Cyclophosphamide, Rituximab
3rd line

16. Azathioprine, Corticosteroids (syst. Or intraarticular) 2nd line
Table 6: Summary of evidence-based algorithmic treatment for Articular Behcet’s disease.
Colchicine, Colchicine + Benzathine penicillin, or anti-inflammatory analgesics
1st line
Azathioprine, Corticosteroids (syst. Or intraarticular)
2nd line
Methotrexate, Salazopyrine, IFN-α,
Anti-TNF-α
3rd line

17. Corticosteroids, Azathioprine, Cyclophosphamide (monthly pulse dose)
Table 7: Summary of evidence-based algorithmic treatment for Vasculo-Behcet’s disease.
Corticosteroids, Azathioprine, Cyclophosphamide (monthly pulse dose)
1st line
Anti-TNF-α
2nd line
Anticoagulation, Antiplatelets, Surgery
3rd line

18. Azathioprine, cyclophosphamide, Anti-TNF-α, IFN-α 2nd line
Table 8: Summary of evidence-based algorithmic treatment for Neuro-Behcet’s disease.
Corticosteroids
1st line
Azathioprine, cyclophosphamide,
Anti-TNF-α, IFN-α
2nd line
Methotrexate, Anticoagulation
3rd line

19. Sulfasalazine, corticosteroids 1st line
Table 9: Summary of evidence-based algorithmic treatment for Gastrointestinal-Behcet’s disease.
Sulfasalazine, corticosteroids
1st line
Azathioprine
2nd line
Anti-TNF-α
3rd line

20. 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.

21. Thanks for your listening