Transcript Document
ميحرلا نمحرلا الله مسب ميلع ملع يذ لك قوفو ميظعلا الله قدص
New Evidence Based 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: 3 rd – 4 th 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 Positive pathergy test 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 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 Colchicine versus Colchicine + Benzathine penicillin Rebamipide versus placebo 1mg/d 1mg/d; 1.2MU/mo.
300 mg/d Decrease in overall disease activity index and significant improvement in OUs, GUs, PPLs, and EN in both sexes, (169pt.) (Davatchi et al.) 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) Reduces the number of OUs and pain 65%, prevent recurrence, no S/E. (35pt. For 3-6mo.) (Matsuda et al.) Zinc sulfate versus placebo Dapsone versus placebo Thalidomide versus placebo 300 mg/d 100 mg/d 100–300 mg/d Significant improvement in the clinical manifestations index of mucocutaneous lesions without any S/E, (32pt.) (Sharquie et al.) 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.) 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 5mg/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 Anti TNF-a (infliximab, adalimumab, etanercept) Etanercept versus placebo Rituximab versus cytotoxic combination therapy
6 MU/d-3 x/w 3 MU/d for 2wk.
3 MU/3x/wk. for 2yr 25mg twice/wk for 4wk 2 1000-mg courses (15-day interval)
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.
Reduces the occurrence of OUs, nodular skin lesions, and PPLs, (Melikoglo et al.) 40 male.
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 SURGICAL treatment Mucocut., CNS, Ocular Cytoid macular edema Severe GIT, pul.,& CNS Mucocut., Ocular GIT Art. Aneurysms, Bowel perforation, cut. Fistula, Cardiac, & Glucoma.
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.
2 1 st nd line line
∗
Topical: Antimicrobial agents, Sucralfate, Corticosteroids, Pimecrolimus Systemic: Colchicine, Colchicine + Benzathine penicillin
∗
Topical: Anti-inflammatory agents, Amlexanox Systemic: Corticosteroids, Dapsone, Azathioprine, Thalidomide 3 rd 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.
*T
opical Rx as a sole agent should be restricted to those who has mild uveitis (ant. Uveitis)
1 2 st nd line line
∗
Topical: corticosteroids + mydriatics ± cycloplegic agents Systemic: Corticosteroids, Cyclosporine-A, Azathioprine IFN-α, Anti-TNF-α 3 rd line Methotrexate, Mycophenolate mofetil, Cyclophosphamide, Rituximab
Table 6: Summary of evidence-based algorithmic treatment for Articular Behcet’s disease.
1 st line Colchicine, Colchicine + Benzathine penicillin, or anti-inflammatory analgesics 2 nd line Azathioprine, Corticosteroids (syst. Or intraarticular) 3 rd line Methotrexate, Salazopyrine, IFN-α, Anti-TNF-α
Table 7: Summary of evidence-based algorithmic treatment for Vasculo-Behcet’s disease.
1 st line Corticosteroids, Azathioprine, Cyclophosphamide (monthly pulse dose) 2 nd line Anti-TNF-α 3 rd line Anticoagulation, Antiplatelets, Surgery
Table 8: Summary of evidence-based algorithmic treatment for Neuro-Behcet’s disease.
1 st line Corticosteroids 2 nd line Azathioprine, cyclophosphamide, Anti-TNF-α, IFN-α 3 rd line Methotrexate, Anticoagulation
Table 9: Summary of evidence-based algorithmic treatment for Gastrointestinal-Behcet’s disease.
1 st line Sulfasalazine, corticosteroids 2 nd line Azathioprine 3 rd line Anti-TNF-α