Behcet's disease


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Behcet's disease - history, silk road, aetiology, pathology, clinical features, mangement

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Behcet's disease

  1. 1. BEHCET’S DISEASE AND ITS ASSOCIATIONS Moderator : Dr. Puneet Bhargava
  2. 2. INTRODUCTION • First described in 1937 by Hulusi Behcet, • As classic trisymptom complex of hypopyon, iritis, and orogenital aphthosis. • Greek physician Adamantiades had reported disease 6 years earlier, as Adamantiades Behcet disease. • First description probably predates both of these by 2500 years. Hippocrates (460–377 BC) describes an endemic disease in Asia Minor characterised by “aphthous ulcerations,” “defluxions about genital parts,” “watery ophthalmies of a chronic character and “large herpetic lesions.”
  3. 3. • Chronic, relapsing-remitting, occlusive vasculitis affecting multiple organ systems • Characterized by oral and genital ulcerations (sores), uveitis, skin rashes, arthritis, thrombophlebitis, colitis, and neurologic symptoms. • Histologically, there is a combination of a perivascular neutrophilic or lymphocytic infiltration, endothelial cell damage or swelling, fibrinoid necrosis coupled with a pro-thrombotic tendency BEHCET’S DISEASE
  4. 4. BEHCET’S: EPIDEMIOLOGY • Prevalence and expression vary geographically, much higher in latitudes between 30° and 45° North, • Around Mediterranean basin extending through Middle East and Orient • Striking similarity of distribution to ancient Silk Road • Suggests that an inherited tendency to develop BD was spread by merchants who traveled these trading routes.
  5. 5. • Turkey has the highest prevalence: 80 to 370 cases per 100,000 population. • Japan, Korea, China, Iran, and Saudi Arabia ranges from 13.5 to 20 cases per 100,000 • Much lower in Western countries. • United States 0.33 per 100,000
  6. 6. • Predominant age: 3rd to 4th decades • Predominant sex: M > F and with more severe disease in some Mediterranean areas. • In Iran, M:F ratio was 24:1 among 1712 patients. • In Turkey, ratio was 16:1 among 427 patients. • Genetics: One report in a mother and newborn (A. Fam, Ann Rheumatic Dis 1981; 40:509-512). Very rarely familial.
  7. 7. Mortality/Morbidity • Chronic morbidity is typical; leading cause is ophthalmic involvement, which can result in blindness. • Effects of disease may be cumulative, especially with neurologic, vascular, and ocular involvement. • Mortality rate is low, but death can occur from neurologic involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy.
  8. 8. PATHOPHYSIOLOGY • Cause is not known • Immunogenetics, immune regulation, vascular abnormalities, or bacterial and viral infection may have a role
  9. 9. BD is associated with multiple hereditary and environmental risk factors.
  10. 10. HLA-B51 and the Silk Road • A heritable risk factor first identified in 1982 • HLA-B*5 locus includes family of HLA-B51 and HLA- B52. • In majority of racial groups, greatest heritable risk factor for disease and severity, is HLA B51. • 21 different alleles may exist at HLA-B*51 locus (B*5101, 5102, etc) • Both B*5101 and B*5108 are associated. • HLA-B*52, which differs from HLA-B*51 by only two amino acids in peptide binding groove, is not associated with BD in any population, suggesting selective peptide binding
  11. 11. • Geographical distribution of HLA-B*51 among healthy subjects roughly corresponds with global disease distribution • But 1/3 of patients, even in countries with a high disease prevalence, do not possess this gene. • In Japanese series prevalence of HLA B51 is only 57% (Mizuki et al., 1997). • There is some evidence that HLA B51, as well as B12, B15, B27, B57, DR2, and DR7 may bear a relationship disease • A possible explanation for these data is that HLA-B*51 molecule expresses Bw4 motif, which itself may be causally related to disease,
  12. 12. Global distribution of HLA-B51 among healthy ethnic control groups with reference to the Silk Road and early demographic movements.
  13. 13. Immunogenetics 1. HLA-B51 or its B101 allele is significantly associated 2. MICA allele • Polymorphic MHC class I–related A gene (MICA) family. • Significantly associated with BD (74%), compared with controls (45.6%) in Japan. • A recent study of 23 Japanese patients showed a strong association with HLA-B51 • Association b/w MICA6 and BD may be a secondary phenomenon related to HLA-B51 3. MEFV gene mutations, Seen in persons with Mediterranean fever, found associated with vascular BD
  14. 14. Human MHC on short arm of chromosome 6. TAP = transporter of antigenic peptides; 21-OH = steroid 21-hydroxylase enzyme; Bf = properdin factor B of the alternate complement pathway; LT = lymphotoxin.
  15. 15. Putative role of MICA molecules and HSP expressed on mucosal epithelial cells. *MHC class I chain related (MIC) gene locus is situated adjacent to HLA-B domain. MICA is expressed at gastrointestinal epithelial surfaces in response to bacterial infection. γδ T cells and NK cells are upregulated, recognise and kill MICA transfected cells. MICA ligand for NKG2D, also expressed on γδ T cells and NK cells.
  16. 16. 4. Levels of TNF-alpha reported significantly elevated • Park et al analyzed TNF-alpha haplotypes in promoter response element that affect binding affinity of certain transcription factors. • Showed TNF-alpha -1031*C, -863*A, -857*C, and -308*G alleles significantly associated and useful in identifying more susceptibles 5. ERAP1 variant Associated with BD processes microbial proteins in such a way that they can be loaded onto HLA-B51 molecule to trigger an abnormal immune response 6. A significant association of BD with variants near CCR1, KLRC4, AND STAT4 gene also found 7. Single nucleotide polymorphism (SNP) • Gene encoding protein tyrosine phosphatase type 22 (PTPN22 620W) has an inverse relationship with BD
  17. 17. 6. Killer inhibitory receptors (KIR) • TCRs, expressed mainly by NK cells and γδ TCR+ T cells • Inhibit cell mediated toxicity. • Binds to molecular sequences which are also found in some HLA class I molecules, including HLA-B51. • An expansion of CD8+ cells, γδ TCR+ cells, and NK cells has been reported • This has led to suggestion that host MHC class I haplotype (HLA-B*51) may “fine tune” the regulation of KIR expression.
  18. 18. Viral and bacterial infection • Aetiology of BD have focused predominantly on herpes simplex virus infection, streptococcal infection, and autoimmunity or cross-reactivity b/w microbial and oral mucosal antigens. • Behcet suggested HSV as a causative agent • PCR studies have remarkably improved diagnostic significance of viral infections, especially HSV. • HSV DNA has been detected in saliva, genital ulcers, and intestinal ulcers in BD Pts. • BD–like symptoms have been induced in an Institute for Cancer Research mouse after inoculation of HSV into its earlobe.
  19. 19. • Acquired hypersensitivity to streptococcal antigens plays an important role in etiopathology of BD • 65-kd microbial HSP, shows significant homology with human 60-kd mitochondrial HSP. • Uncommon serotypes of Streptococcus sanguis found in BD, cross- react with 65-kd HSP, which also shares antigenicity with an oral mucosal antigen. Role of bacterial and human heat shock protein (HSP) 60/65 as T cell antigens in BD
  20. 20. •T cell responses against retinal S- Ag are present in various types of human uveitis, including BD An immunological model for role of cross reactive retinal-S antigen (S-Ag) and HLA-B27/51 derived peptides in chronic posterior uveitis of BD
  21. 21. T-cell epitope mapping has identified 4 peptides derived from sequence of 65-kd HSP that specifically stimulates TCR+ lymphocytes from patients with BD. • These peptides (111-125, 154-172, 219-233, and 311-325) show significant homology with corresponding peptides (136-150, 179- 197, 244-258, 336-351) derived from human 60-kd HSP. • B-cell epitopes within mycobacterial HSP65 or human HSP60 overlap with T-cell epitopes, and both IgG and IgA antibodies have been identified. • Among 4 T- and B-cell epitopes, peptide 336-351 of 60-kd HSP is significantly associated with BD in Britain, Japan, and Turkey. • HSP60/65 found significantly increased in epidermal cells of BD skin lesions, • Antibody levels to HSP65 were significantly elevated in CSF neurological BD
  22. 22. Immunological abnormalities • Th1 cytokine IFN-y level is elevated in serum, in skin T cells, and cerebrospinal fluid, • IL–12 is generated by the stimulation of CD4 -T cells with HSP peptide 336-351, • IL-12 can also be secreted by neutrophils • Th2 cytokine IL-6 is also increased in active disease • Stimulation with S sanguis (KTH-1) of T-cell lines generated from patients with BD suggests that Th1-type mRNA is induced (IL-2 and IFN). • Investigations of intracellular IFN and IL-4 suggest that polarization toward Th1 type of cells occurs in patients with active BD b/c of a significant increase in intracellular IFN that was not observed with IL-4. • Converse was found in another investigation by stimulating peripheral blood mononuclear cells, with increased Th2 cytokines (IL-10 and decreased IL-2 or IFN) in active Behçet disease.
  23. 23. • Intracellular adhesion molecule 1 was enhanced in human dermal microvascular endothelial cells after treatment with serum from patients with BD, and this may have induced increased adhesion of T cells to endothelial cells. • Levels of proinflammatory cytokines TNF– alpha, TNF receptor 1, IL-1, and IL-8 are elevated and remain unregulated in peripheral blood mononuclear cells and neutrophils • Levels of IL-10 and IL-13 may also be elevated. • IL-23 p19 mRNA has been detected in erythema nodosum- like lesions of BD • Plasma levels of vascular endothelial growth factor is significantly higher • Neopterin (marker of cellular immune activation) • Produced by human monocytes and macrophages in response to interferon-gamma (IFN-gamma) released from activated T cells • Kose et al showed that serum levels of neopterin were significantly higher in active and inactive BD patients than in controls. • Polymorphisms in toll-like receptor 4 have been associated
  24. 24. Endothelial and vascular dysfunctions • Vascular changes leading to vasculitis and thrombosis are important pathological feature • A recent study proposes that immunoglobulin to carboxy- terminal subunit of Sip1 (Sip1 C-ter) may be a useful novel autoantigen • Level was elevated in 41% of BD patients, and in 45% of primary vasculitis patients, pointing at endothelial dysfunction in vasculitis.[ • Antiendothelial cell antibodies significantly increased • T cells (mostly CD4 cells), B cells, and neutrophils are infiltrated perivascularly. • Esmat et al showed much higher serum lipoprotein(a) levels in patients with vascular complications and lower levels of serum nitrites during disease activity.[
  25. 25. • Association of factor V Leiden and G20210A prothrombin mutation with thrombosis in BD patients is also seen • Prostanoid synthesis in endothelial cells or vessel walls is impaired, whereas von Willebrand factor, thromboxane, and thrombomodulin are increased. • Level of endothelin 1 and 2 is increased in patients with vascular involvement. • Endothelial cell–dependent vasodilator function is significantly impaired • Thrombin activatable fibrinolysis inhibitor levels are higher, possibly contributing to increased thrombosis
  26. 26. History • Signs and symptoms may be recurrent, may precede onset of mucosal membrane ulcerations by 6 months to 5 years. • Prior to onset of disease, patients may experience a variety of symptoms. • Malaise • Anorexia • Weight loss • Generalized weakness • Headache • Perspiration • Decreased or elevated temperature • Lymphadenopathy • Pain of the substernal and temporal regions • A history of repeated sore throats, tonsillitis, myalgias, and migratory erythralgias without overt arthritis is common.
  27. 27. spectrum of organ involvement in behçet’s disease.
  28. 28. Diagnostic criteria from the Behçet syndrome research committee of Japan (1987 revision) Diagnosis a) Complete – Four major features b) Incomplete – (1) 3 major features, (2) 2 major and 2 minor features, (3) Typical ocular symptom and 1 major or 2 minor features c) Possible – (1) 2 major features (2) 1 major and 2 minor features • Major features • Recurrent aphthous ulceration of oral mucous membrane • Skin lesions -Erythema nodosum – like lesions, subcutaneous thrombophlebitis, folliculitis (acnelike lesions), cutaneous hypersensitivity • Eye lesions - Iridocyclitis, chorioretinitis, retinouveitis, definite history of chorioretinitis or retinouveitis • Genital ulcers • Minor features • Arthritis without deformity and ankylosis • Gastrointestinal lesions characterized by ileocecal ulcers • Epididymitis • Vascular lesions • Central nervous system symptoms
  29. 29. • Recurrent oral ulceration - Minor aphthous or major aphthous or herpetiform ulceration observed by a physician or reported reliably by a patient that recurs at least 3 times in one 12-month period plus 2 of the following: • Recurrent genital ulceration – Recurrent genital aphthous ulceration or scarring, especially males, observed by a physician or reliably reported by a patient • Eye lesions – (1) Anterior uveitis, posterior uveitis, and cells in vitreous upon slit-lamp examination or (2) retinal vasculitis observed by physician (ophthalmologist) • Skin lesions – (1) Erythema nodosum–like lesions observed by physician or reliably reported by a patient, pseudofolliculitis, and papulopustular lesions or (2) acneiform nodules consistent with Behçet disease, observed by a physician, and in postadolescent patients not receiving corticosteroids • Positive pathergy test – An erythematous papule larger than 2 mm at prick site 48 hours after application of a 20- to 22-gauge sterile needle, which obliquely penetrated avascular skin to a depth of 5 mm as read by a physician at 48 hours Findings are applicable if no other clinical explanation is present. International criteria for the classification of Behçet disease (1990)
  30. 30. Physical • Oral ulcers (100%) • Indistinguishable from common aphthae (canker sores). • Aphthae may be more extensive, more painful, more frequent, and evolve quickly from a pinpoint flat ulcer to a large sore. • Lesions can be shallow or deep (2-30 mm in diameter) and usually have a central, yellowish, necrotic base and a punched- out, clean margin. • Appear singly or in crops, located anywhere in the oral cavity, persist for 1-2 weeks, and subside without leaving scars. • M/c sites - tongue, lips, buccal mucosa, and gingiva; • Tonsils, palate, and pharynx are less common sites. • Interval b/w recurrences ranges from weeks to months. • 3 types:
  31. 31. Minor ulcer Consists of 1-5 small, moderately painful ulcers persisting for 4- 14 days Major ulcer 1-10 very painful ulcers, measuring 10-30 mm, persisting up to 6 weeks, and possibly leaving a scar upon healing Herpetiform ulcer Recurrent crop of as many as 1000 small and painful ulcers
  32. 32. Genital manifestations • Genital ulcers (90%, M>F) resemble their oral counterparts but cause greater scarring. • In males, usually occur on scrotum, penis, and groin. • In females, occur on vulva, vagina, groin, and cervix • Ulcers may found in urethral orifice and perianal area. • Epididymitis may arise in men • Orchiepididymitis,10.8% of men.
  33. 33. Cutaneous manifestations(58.6-97%)  A variety of skin lesions may appear,  Eg.- Sweet syndrome–like lesion. Papulopustular eruptions (55-83%, M>F) Erythema nodosum–like lesions (44-62%, F>M)
  34. 34. Cutaneous manifestations • Erythema multiforme–like lesions • Thrombophlebitis • Ulcers • Bullous necrotizing vasculitis • Pyoderma gangrenosum • Pathergy reaction • Erythematous papule larger than 2 mm develops at prick site after 48 hours • Higher positivity (84-98%) is found in Mediterranean areas and Middle East than in Far East (40-70%), • Western countries having significantly lower positivity Typical positive pathergy reaction at injection site
  35. 35. Ocular manifestations(47-65%) • Eye disease is usually present from outset but also may develop within first few years. • Major cause of morbidity and most dreaded complication b/c it occasionally progresses rapidly to blindness. • Childhood-onset Behçet uveitis is more common in males. • Most diagnostically relevant lesion is posterior uveitis, ie, retinal vasculitis • Other include anterior uveitis, iridocyclitis, chorioretinitis, scleritis, keratitis, vitreous hemorrhage, optic neuritis, conjunctivitis, retinal vein occlusion, and retinal neovascularization. • Hypopyon, considered hallmark of BD, is now uncommon.
  36. 36. • Decreased visual acuity is a result of secondary glaucoma, cataracts, or vitreous hemorrhage. • Blindness has been reported to occur within 4-5 years from onset of ocular symptoms. • Retinal vein thrombosis leading to sudden blindness is not rare. • Saadoun et al found that cerebral venous thrombosis (CVT) was present in 7.8% of a large cohort of patients with BD. • Main complication of CVT was severe visual loss from optic atrophy.
  37. 37. Inflammatory retinal vein occlusion with associated vitritis and retinal vasculitis before (A) and after (B) treatment with high dose oral steroid. Anterior segment complications of retinal vein occlusion: retinal ischaemia with secondary rubeosis iridis. (A) Acute branch retinal vein occlusion. (B) Total vascular obliteration and optic atrophy secondary to recurrent vascular occlusion.
  38. 38. Ocular involvement showing posterior uveitis. HYPOPYON – pus in the anterior chamber associated with uveitis
  39. 39. Vascular involvement • Occurs in 30-50%, mostly men. • H/P- media thickening, elastic fiber splitting, and perivascular round cell infiltration. • 4 types of vascular lesions – • Aterial and venous occlusions, aneurysms, and varices. • Venous inv. M/C occlusion, rarely varices. • M/C sites - SVC,IVC, deep femoral vein, and subclavian vein.
  40. 40. Vascular involvement • Arterial complications, 7% , M/C Aneurysm and occlusion • Subclavian and pulmonary artery, M/Cly occluded. • Different clinical presentations A/t site • Pulseless disease -subclavian artery occlusion. • Hypertension - renal artery stenosis. • Femoral artery stenosis - intermittent claudication, AVN of femoral head. • Pulmonary vasculitis- dyspnea, chest pain, cough hemoptysis. • Aneurysm accounts for most vascular deaths. • Common sites- abd. aorta, femoral and thoracic artery.
  41. 41. • Gastrointestinal involvement (>10%) • Clinical spectrum is enormously varied • Anorexia, vomiting, dyspepsia, diarrhea, abdominal distention, and abdominal pain • Cardiac manifestations (5-17%) • Coronary vasculitis and thrombosis, pericarditis, myocarditis, endocarditis with granulomatous changes or fibrosis, regurgitation, and diastolic dysfunction • Lung involvement (up to 18%) • Pulmonary vasculitis, hypertension, pleural effusions and Aneurysms
  42. 42. Joint manifestations (30 - 40%) • More than half patients develop signs or symptoms of synovitis, arthritis, and/or arthralgia during course of disease. • Most frequent minor feature in childhood-onset BD is reported to be arthritis, occurring in 11 of 40 patients. • Multiple-joint involvement is common. • Clinical features have been reported as pain, tenderness, swelling, limitation of joint movement, warmth, and morning stiffness.
  43. 43. Neurologic manifestations (3.2-49%) • May present as meningoencephalitis, a multiple sclerosis–like illness, acute myelitis, stroke, or pseudotumor cerebri. • Most serious, leading to severe disability and a high fatality rate. • Usually occur within 5 years of disease onset. • Severe headache is most frequent initial symptom. • Three categories (Pallis and Fudge (1956) and Wadia and Williams (1957) (1) Brain stem syndrome, A/w fever, arthralgia and skin eruption; brainstem signs developes subacutely with evolving cranial neuropathies, ocular motor dysfunction, nystagmus and gaze palsies, dysarthria and ataxia, bulbar muscle weakness, Headache with meningism, CSF pleocytosis and high protein content (2) Meningomyelitis syndrome, Meningitis with spinal cord and hemisphere signs (Silfverskiold, 1951) (3) Organic confusional syndrome, Meningoencephalitis without focal neurological signs, some times chronic and progressive, resulting ultimately in dementia, Parkinsonism, pseudobulbar palsy and quadriparesis
  44. 44. Pregnancy-associated manifestations • Pregnant women may experience more severe symptoms during first trimester. • Overall, pregnancy does not seem to markedly affect the course of BD. • Close follow-up is necessary to monitor the health of mother and baby.
  45. 45. Differential Diagnoses • Acute Febrile Neutrophilic Dermatosis • Pyoderma Gangrenosum • Cyclic neutropenia • Aphthous Stomatitis • Erythema Multiforme • SJS-TEN • Erythema Nodosum • Viral infections • Herpes Simplex, coxsackie, echo • Syphilis and other STIs • Lupus Erythematosus, Acute • Reiter disease • VKH syndrome • Bullous autoimmune diseases • JRA • Sarcoidosis • Multiple sclerosis • Ulcerative colitis, crohn disease
  46. 46. Laboratory Studies • Mild anemia and leukocytosis in chronic disease. • ESR, C-reactive protein value, and other acute phase reactants may be elevated during the active didease, but they do not correlate well with clinical activity. • IgA, IgG, alpha-2 globulin, IgM, and immune complexes are occasionally elevated. • Rheumatoid factor and antinuclear antibodies are absent. • Antineutrophil cytoplasmic antibody and antiphospholipid antibody test results are usually negative.
  47. 47. Histologic Findings • Vasculitis is thought to affect vessels of all sizes; various skin lesions are thought to be secondary to small vessel vasculitis. • H/P is variable, dependent upon type of lesion. • Pathergic lesions:- Characterized by a heavy neutrophilic infiltrate without fibrin within vessel walls. • Erythema nodosum–like lesions:- Show a perivascular lymphocytic infiltrate in deep dermis and septa with a lymphocytic vasculitis but lack histiocytic granulomas of typical erythema nodosum. • Aphthous ulcers have a nonspecific pathology with a variable infiltrate of lymphocytes, macrophages, and neutrophils at base of ulcer. • T-cell subsets with a preponderance of helper-inducer cells over T suppressor- cytotoxic cells have been observed in lesions. Histology of ulcers revealing neutrophilic infiltrate and vasculitis
  48. 48. Electron microscopic observations • Erythema nodosum–like lesions shows microvascular changes and lymphocyte-mediated fat cell lysis. • Small dermal blood vessels embolized by thrombi are observed at sites of needle prick reaction (pathergy) and at erythema nodosum–like lesions. • Early changes in fat cells may be caused by vascular changes brought about by the specific degeneration of endothelial cells and vascular stenosis a/w delayed- type hypersensitivity reaction.
  49. 49. BD needs multidisciplinary approach • Dermatologist - For evaluation of mucocutaneous lesions (ie, oral ulcer, genital ulcer, skin lesions) • Ophthalmologist - For evaluation of eye involvement • Rheumatologist or orthopedic surgeon - For evaluation of joint involvement • Neurologist or psychiatrist - For evaluation of CNS involvement • Internal medicine specialist - For evaluation of gastrointestinal, pulmonary, renal, or endocrine involvement • General surgeon - For evaluation of gastrointestinal involvement • Chest surgeon or cardiologist - For evaluation of cardiovascular involvement • Ear, nose, and throat specialist or dentist - For evaluation of oral cavity
  50. 50. Medical Care • Treatment of BD symptomatic and empiric. • Choice of treatment depends on site and severity of clinical manifestations
  51. 51. Local therapy  Recurrent aphthae • mild diet, avoidance of irritating agents, • Caustic solutions (silver nitrate, 1%-2%; tinctura myrrha, 5%-10% weight/volume; H202,0.5%; methylviolet,0.5%) 1-2xld • Antiseptic and anti-inflammatory preparations (amlexanox, 5% in oral paste; triclosan, 0.1% mouthwash solution and in toothpaste ), 3% diclofenac in 2.5% hyaluronic acid, tetracycline mouthwash • Corticosteroids (triamcinolone mucosal ointment, dexamethasone mucosal paste, betamethasone pastilles) 4 x/day or during night (ointment / paste) or intrafocal infiltrations with triamcinolone suspension 0.1-0.5 mL per lesion • Anaesthetics (lidocaine - 2%-5%; mepivacaine - 1.5%, tetracaine - 0.5%-1% gels or mucosal ointments) 2-3 x/day • 5-Aminosalicylic acid (5% cream) 3 x/day (reduces the duration of lesions and the pain • Sucralfate suspension, 5 mL x 4/day (for oral aphthous and genital ulcers) • Topical tacrolimus, nicotine patches, and topical G-CSF
  52. 52.  Genital ulcers and skin lesions, • Corticosteroid and antiseptic creams for 7 days. • Painful genital ulcerations topical anaesthetics in cream. • Corticosteroid injections (triamcinolone, 0.1 to 0.5 ml/lesion) in recalcitrant ulcerations.
  53. 53. Systemic therapy • Corticosteroids • Mainstay for all clinical manifestations. • Have a beneficial effect on acute manifestations, no definite evidence effectiveness in controlling progression. • Adverse effects of long-term therapy must be considered. • Mucocutaneous lesions and arthritis:- • NSAIDs, zinc sulfate, levamisole, colchicine, dapsone, or sulfapyridine and thalidomide. Immunosuppressive therapy with azathioprine, chlorambucil, or cyclophosphamide • Uveitis and CNS involvement:- • Systemic corticosteroids, azathioprine, or cyclosporine, MTx • In CNS involvement, risks and benefits of cyclosporine need to be considered b/c of neurological side effects.
  54. 54. • Anticoagulants are given to patients with thromboses. • Other therapeutic approaches • IFN alfa, IFN gamma, acyclovir, high-dose corticosteroids or cyclophosphamide pulse therapy, and tacrolimus • Japanese tacrolimus study group reported that tacrolimus was effective in treating refractory uveitis in a dosage-dependent manner. • Adverse effects were renal impairment (28.3%), neurologic symptoms (20.8%), gastrointestinal symptoms (18.9%), and hyperglycemia (13.2%).
  55. 55. • Subcutaneous IFN alfa-2a therapy • resulted in reduced ulcers and eye disease. • Flulike symptoms were most common adverse effect. • Leukopenia, hair loss, and development of antinuclear and antithyroid antibodies were reported less commonly. • A patient presenting with oral ulcers resistant to prednisone, azathioprine, colchicine, dapsone, and cyclosporin responded well to lenalidomide. • A patient with Behçet disease with ocular involvement, dependant on corticosteroids and refractory to azathioprine, showed improvement with addition of pentoxifylline
  56. 56. • A case of Behçet disease resistant to prednisolone, cyclosporin, azathioprine, infliximab with methotrexate, and colchicine has been successfully treated with anakinra. • infliximab, and etanercept, have decreased frequency of attacks • Etanercept has been used at 25 mg twice a week. • Pediatric case responding to infliximab has been reported. • Infliximab has resulted in responses after etanercept failed. • Infliximab infusions of 5-10 mg/kg have been used with variable dosing schedules. • Several patients not responding to infliximab have been treated with adalimumab.
  57. 57. drug doses indication Methylprednisolone 40 mg/every 3 wk lM Erythema nodosum (but not orogenital ulcers) Rebamipide 300 mg/day PO Oral ulcers Colchicine 1-2 mg/day PO Erythema nodosum, arthritis, genital Ulcer s (oral ulcer in female) Dapsone 100 mg/day PO Orogenital ulcers, skin lesions, pathergy Azathioprine 2.5 mg/kg/day Recent onset ocular disease lnterferon-alfa-2a 6x106 lU/3x/wk SC Orogenital ulcers, papulopustular lesions Thalidomide 100 mg/day Orogenital ulcers, Papulopustular lesions CyclosporinA 10 mg/kg/day PO Ocular manifestations, skin lesions, orogenital ulcers Etanercept 25 mg/2 x/wk P0 Oral ulcers, papulopustular lesions nodular lesions, (not pathergy test)
  58. 58. Behcet’s Disease: Prognosis • Behcet's disease has an undulating course of exacerbations and remissions, and may become less severe after approximately 20 years. • Appears to be more severe in young, male, and Middle Eastern or Far Eastern patients.
  59. 59. THANK YOU