Evaluation &Evaluation &
Management ofManagement of
MucocutaneousMucocutaneous
UlcerationUlceration
Ami A. Shah, MDAmi A. ...
ObjectivesObjectives
 Discuss the differential diagnosis andDiscuss the differential diagnosis and
recommended evaluation...
History of Present IllnessHistory of Present Illness
 34 year-old African American woman with34 year-old African American...
History of Present IllnessHistory of Present Illness
 June 2004:June 2004:
 Hospitalized at Bayview for 4 days for sever...
Clinical Course 2004Clinical Course 2004
 August 2004:August 2004:
 Dermatology evaluation for recurrent furuncles after...
Clinical Course 2004Clinical Course 2004
 September 2004:September 2004:
 2 small erosions on the mons pubis and also on...
Clinical Course 2004Clinical Course 2004
 October 2004:October 2004:
 3-week period of no oral or genital lesions while ...
Clinical Course 2004Clinical Course 2004
 December 2004:December 2004:
 Infectious Disease evaluation: 1 x 1.5 cm inner ...
Evolution of symptomsEvolution of symptoms
 March 2005 – Dermatology visit:March 2005 – Dermatology visit:
 On BID Bactr...
Evolution of symptomsEvolution of symptoms
 April 2005 – ID visit:April 2005 – ID visit:
 Now two persistent vaginal ulc...
Gynecology Admission 2006Gynecology Admission 2006
 October 2006:October 2006:
 10/9: Presented to urgent care with geni...
Past Medical HistoryPast Medical History
 Polycystic ovarian syndrome s/p laparoscopyPolycystic ovarian syndrome s/p lapa...
Medications, Allergies, Family &Medications, Allergies, Family &
Social HistorySocial History
 Medications: pHisoHex, lid...
Physical ExaminationPhysical Examination
 Tm 39.2, wt 44.9 kgTm 39.2, wt 44.9 kg
 CachecticCachectic
 Numerous open com...
Physical ExaminationPhysical Examination
 2/6 systolic murmur LLSB and apex2/6 systolic murmur LLSB and apexaxillaaxill...
Physical ExaminationPhysical Examination
www.rheumtext.com - Hochberg et al (eds)
Ophthalmic EvaluationOphthalmic Evaluation
 10/22: Wilmer ER10/22: Wilmer ER
 Concern for bilateral intermediate uveitis...
Gynecologic, GI, ID, and ImagingGynecologic, GI, ID, and Imaging
EvaluationEvaluation
 10/24: OR for wound debridement, a...
Evaluation ofEvaluation of
MucocutaneousMucocutaneous
UlcerationUlceration
BehBehçet’s Diseaseçet’s Disease
 Multisystem inflammatory disorderMultisystem inflammatory disorder
 Described in 1937 ...
Diagnosing BehDiagnosing Behçet’s: Internationalçet’s: International
Study Group (ISG) CriteriaStudy Group (ISG) Criteria
...
Performance of ISG CriteriaPerformance of ISG Criteria
 Criteria derived by consensus from 914 patientsCriteria derived b...
Frequency of the ClinicalFrequency of the Clinical
Manifestations of Behçet’s SyndromeManifestations of Behçet’s Syndrome
...
Complex AphthosisComplex Aphthosis
 Required for diagnosis:Required for diagnosis:
 Near constant presence of multiple o...
The Wake Forest ExperienceThe Wake Forest Experience
1995-20011995-2001
81 patients referred for evaluation of Behçet’s
10...
The Wake Forest ExperienceThe Wake Forest Experience
1995-20011995-2001
 10/12 with 210/12 with 2° aphthosis had IBD° aph...
Diagnostic ApproachDiagnostic Approach
Letsinger, J.A. et. al. J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):500-8.
Differential Diagnosis of Behçet’sDifferential Diagnosis of Behçet’s
SyndromeSyndrome
Vulvar Ulceration in Crohn’s DiseaseVulvar Ulceration in Crohn’s Disease
 Many case reports of Crohn’sMany case reports o...
Systemic MedicalSystemic Medical
Management ofManagement of
Mucocutaneous Ulcers inMucocutaneous Ulcers in
Behçet’sBehçet’s
CorticosteroidsCorticosteroids
 86 patients with active Behçet’s and at least one genital
ulcer occurring within the prec...
CorticosteroidsCorticosteroids
 Randomized to 40mg methylprednisolone IM or
placebo saline injections Q3 weeks for 27 wee...
Results & Primary OutcomesResults & Primary Outcomes
 76 patients (88%) completed the
treatment
 One male from each grou...
Erythema Nodosum andErythema Nodosum and
CorticosteroidsCorticosteroids
 Clinical characteristics at baseline similar in ...
ColchicineColchicine
 116 patients with Behçet’s (60 M/56 F) with active116 patients with Behçet’s (60 M/56 F) with activ...
ColchicineColchicine
 Secondary outcome measure: Difference in theSecondary outcome measure: Difference in the
number of ...
Colchicine ResultsColchicine Results
• Efficacy not the same between males and females
• Colchicine clearly effective for ...
LevamisoleLevamisole
 Open trial of 11 (3M, 8F) patients: 2 with completeOpen trial of 11 (3M, 8F) patients: 2 with compl...
MethotrexateMethotrexate
 Report of 2 patients with Behçet’s and active mucocutaneousReport of 2 patients with Behçet’s a...
ThalidomideThalidomide
 Randomized, double-blind, placebo-controlled trial inRandomized, double-blind, placebo-controlled...
ThalidomideThalidomide
 For data collection, only the number of new lesions wasFor data collection, only the number of ne...
Complete Response:

Thalidomide, 100 mg/d: 2/32 (6%)

Thalidomide, 300 mg/d: 5/31 (16%)

Placebo: 0/32
Most treatment f...
Diamonds = placebo; squares = 100-mg/d thalidomide; triangles = 300-mg/d thalidomide.
Mean differences in mucocutaneous le...
AzathioprineAzathioprine
 No significant data looking at effectiveness ofNo significant data looking at effectiveness of
...
AzathioprineAzathioprine
 Corticosteroid treatment available to allCorticosteroid treatment available to all
 6 patients...
Extraocular ManifestationsExtraocular Manifestations
ManifestationManifestation Ever PresentEver Present Present atPresent...
CyclosporineCyclosporine
 96 patients, age ≥ 15, with complete or incomplete96 patients, age ≥ 15, with complete or incom...
CyclosporineCyclosporine
 Oral aphthous ulcers, dermal lesions, and genital ulcersOral aphthous ulcers, dermal lesions, a...
CyclosporineCyclosporine
 Longer term study in 36 patients with complete orLonger term study in 36 patients with complete...
CyclosporineCyclosporine
 30 Behçet’s patients with pathergy and active30 Behçet’s patients with pathergy and active
muco...
CyclosporineCyclosporine
 Oral ulcers in 24/24 pretreatmentOral ulcers in 24/24 pretreatment
 Symptom free intervals inc...
InterferonInterferon αα-2a-2a
 50 patients with BD by ISG criteria (19 females, 31 males)50 patients with BD by ISG crite...
InterferonInterferon αα-2a-2a
 Complete response:Complete response:
 disappearance of all signs and symptomsdisappearanc...
InterferonInterferon αα-2a-2a
 Stable disease:Stable disease:
 < 50% change in clinical signs and< 50% change in clinica...
InterferonInterferon αα-2a-2a
 Six patients (2 in IFN group and 4 in placebo) did not complete theSix patients (2 in IFN ...
EtanerceptEtanercept
 Presence of T cell, monocyte, and macrophage
infiltration and the expression of IFN-γ and IL-12
sug...
EtanerceptEtanercept
 Double blind, placebo controlled trial to evaluate the effect of
etanercept on pathergy and MSU rea...
EtanerceptEtanercept
 40 patients randomized to etanercept 25mg BIW or placebo for 4
weeks
 Drug washout: 18 patients wh...
EtanerceptEtanercept
• Statistically significant improvement in oral ulcers and nodular lesions by week 1,
but benefit not...
Response to Infliximab afterResponse to Infliximab after
Etanercept FailureEtanercept Failure
 38-yr-old Caucasian woman ...
Response to Infliximab afterResponse to Infliximab after
Etanercept FailureEtanercept Failure
 Switched to infliximab 3 m...
Infliximab for Recurrent OrogenitalInfliximab for Recurrent Orogenital
Ulceration in Behçet’sUlceration in Behçet’s
 Case...
InfliximabInfliximab
 40 year old man diagnosed with PAN in 1986 due to40 year old man diagnosed with PAN in 1986 due to
...
InfliximabInfliximab
 September 1999: oral, anal, and penile ulcers; treatedSeptember 1999: oral, anal, and penile ulcers...
Infliximab for Recurrent OrogenitalInfliximab for Recurrent Orogenital
Ulceration in Behçet’sUlceration in Behçet’s
 39 y...
Infliximab for Recurrent OrogenitalInfliximab for Recurrent Orogenital
Ulceration in Behçet’sUlceration in Behçet’s
 Infl...
 Randomized, multicenter, double-blind, placebo-Randomized, multicenter, double-blind, placebo-
controlled trial of infli...
 Primary end point: ≥ 50% reduction in the number ofPrimary end point: ≥ 50% reduction in the number of
draining fistulas...
Infliximab in Crohn’s FistulasInfliximab in Crohn’s Fistulas
Present, D.H. et. al. N Engl J Med. 1999; 340(18):1398-405
Relative Contraindications toRelative Contraindications to
Infliximab?Infliximab?
 Open label study of 12 patients treate...
Our CaseOur Case
 Two days into IV steroid pulse, all oral ulcers goneTwo days into IV steroid pulse, all oral ulcers gon...
Future PlansFuture Plans
 Advised smoking cessationAdvised smoking cessation
 Tapered prednisone to 30mg dailyTapered pr...
ReferencesReferences
 Sakane, T., et. al. N Engl J Med. 1999 Oct 21;341(17):1284-91.Sakane, T., et. al. N Engl J Med. 199...
Pre
Pre
Pre
Upcoming SlideShare
Loading in …5
×

Pre

791 views

Published on

Published in: Health & Medicine
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
791
On SlideShare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
15
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide
  • Mean numbers of minor oral ulcers were significantly lower at week 4 in both thalidomide groups than in the placebo group (P &amp;lt; 0.001); this decrease persisted thereafter with no significant changes between the two thalidomide groups.
    The suppressive effect of thalidomide in both groups reached statistical significance for genital ulcers (P &amp;lt; 0.001) and follicular lesions (P = 0.008) at week 8; the two groups did not differ significantly. In contrast, the evaluation done 4 weeks after treatment ended showed increased numbers of mucocutaneous lesions in both thalidomide groups.
    Thalidomide treatment resulted in significant increases in the frequency of erythema nodosum lesions compared with placebo during the first 8 weeks of the trial (for week 4, P = 0.046; for week 8, P = 0.03). The increase in the frequency of erythema nodosum lesions was significantly higher in the 100-mg group than that in the 300-mg group at week 8 (P = 0.03). With the continuation of treatment, however, the frequency of erythema nodosum lesions was similar in all three groups.
  • Pre

    1. 1. Evaluation &Evaluation & Management ofManagement of MucocutaneousMucocutaneous UlcerationUlceration Ami A. Shah, MDAmi A. Shah, MD Disclosures: No Relevant Financial Relationships withDisclosures: No Relevant Financial Relationships with Commercial InterestsCommercial Interests
    2. 2. ObjectivesObjectives  Discuss the differential diagnosis andDiscuss the differential diagnosis and recommended evaluation of mucocutaneousrecommended evaluation of mucocutaneous ulcerationulceration  Discuss current treatment options for severeDiscuss current treatment options for severe diseasedisease  Recognize current limitations of available data:Recognize current limitations of available data: small sample sizes, lack of RCTsmall sample sizes, lack of RCT
    3. 3. History of Present IllnessHistory of Present Illness  34 year-old African American woman with34 year-old African American woman with longstanding furunculosislongstanding furunculosis  January 2004:January 2004:  Worsening furuncles for 1 month which grew MRSAWorsening furuncles for 1 month which grew MRSA  Treated with multiple courses of antibioticsTreated with multiple courses of antibiotics  Developed new, painful oral ulcersDeveloped new, painful oral ulcers
    4. 4. History of Present IllnessHistory of Present Illness  June 2004:June 2004:  Hospitalized at Bayview for 4 days for severe pain due toHospitalized at Bayview for 4 days for severe pain due to furuncles and multiple vulvar ulcers on bilateral labia withfuruncles and multiple vulvar ulcers on bilateral labia with pustular discharge, erythema, and indurationpustular discharge, erythema, and induration  Started on antibiotics as a wound culture grew MRSA  Started on antibiotics as a wound culture grew MRSA    Negative HIV antibody, RPR, Gonorrhea probe, ChlamydiaNegative HIV antibody, RPR, Gonorrhea probe, Chlamydia probe, and HSV cultureprobe, and HSV culture  Discharged on Bactrim and bacitracin given MRSA nasalDischarged on Bactrim and bacitracin given MRSA nasal colonizationcolonization
    5. 5. Clinical Course 2004Clinical Course 2004  August 2004:August 2004:  Dermatology evaluation for recurrent furuncles after bactrimDermatology evaluation for recurrent furuncles after bactrim discontinueddiscontinued  Aphthous ulcer under tongueAphthous ulcer under tongue  On left labia majora, very small, 5-mm pustule with overlyingOn left labia majora, very small, 5-mm pustule with overlying crust on an erythematous background; small adjacentcrust on an erythematous background; small adjacent erosion.  erosion.    Right labia minora, area of erosion with some crust andRight labia minora, area of erosion with some crust and surrounding erythemasurrounding erythema  Prescribed Cleocin lotion and viscous lidocainePrescribed Cleocin lotion and viscous lidocaine  Another HSV culture was negative; routine bacterial cultureAnother HSV culture was negative; routine bacterial culture with genital florawith genital flora  Restarted on BactrimRestarted on Bactrim
    6. 6. Clinical Course 2004Clinical Course 2004  September 2004:September 2004:  2 small erosions on the mons pubis and also on the2 small erosions on the mons pubis and also on the labia majoralabia majora  Aphthous ulcers on lower lip; no obvious furunclesAphthous ulcers on lower lip; no obvious furuncles  Crohn’s, Reiter’s and Behçet’s entered differentialCrohn’s, Reiter’s and Behçet’s entered differential diagnosisdiagnosis  ID referral, HSV culture sent, zovirax creamID referral, HSV culture sent, zovirax cream prescribed and bactrim continuedprescribed and bactrim continued
    7. 7. Clinical Course 2004Clinical Course 2004  October 2004:October 2004:  3-week period of no oral or genital lesions while on3-week period of no oral or genital lesions while on BactrimBactrim  Discontinued BactrimDiscontinued Bactrim  November 2004:November 2004:  Recurrence of sores in 11/04 requiring reinstitutionRecurrence of sores in 11/04 requiring reinstitution of this medicationof this medication
    8. 8. Clinical Course 2004Clinical Course 2004  December 2004:December 2004:  Infectious Disease evaluation: 1 x 1.5 cm inner lip ulcer; threeInfectious Disease evaluation: 1 x 1.5 cm inner lip ulcer; three small, tender furuncles on scalp, 1 x 1 cm ulcer on labia withsmall, tender furuncles on scalp, 1 x 1 cm ulcer on labia with pus, right external vulva well-healed scarspus, right external vulva well-healed scars  Negative viral culture for HSV Negative viral culture for HSV   Pemphigus vulgaris and Behçet's disease again consideredPemphigus vulgaris and Behçet's disease again considered  Anemic with Hgb 10.9 with normal MCV, iron studiesAnemic with Hgb 10.9 with normal MCV, iron studies normal, ESR 20, negative ANA, negative hepatitis C Ab,normal, ESR 20, negative ANA, negative hepatitis C Ab, elevated IgG at 1630, normal IgA and IgM.  elevated IgG at 1630, normal IgA and IgM.    Recommended biopsy by dermatologyRecommended biopsy by dermatology
    9. 9. Evolution of symptomsEvolution of symptoms  March 2005 – Dermatology visit:March 2005 – Dermatology visit:  On BID Bactrim DS since October/NovemberOn BID Bactrim DS since October/November  Now continuous outbreaks of ulcers with all lesions lasting a longerNow continuous outbreaks of ulcers with all lesions lasting a longer durationduration  Vaginal vault with a 1.5-cm, punched-out, erythematous, exquisitelyVaginal vault with a 1.5-cm, punched-out, erythematous, exquisitely tender ulcer present for 2 monthstender ulcer present for 2 months  Well-circumscribed, punched-out, yellow, fibrinous-based ulcer on rightWell-circumscribed, punched-out, yellow, fibrinous-based ulcer on right upper lip growing in size for several weeksupper lip growing in size for several weeks  Multiple comedones, evidence of acne scarring, right cheek 1-cmMultiple comedones, evidence of acne scarring, right cheek 1-cm erythematous noduleerythematous nodule  Considered biopsy, considered accutane, resent HSV antibodiesConsidered biopsy, considered accutane, resent HSV antibodies
    10. 10. Evolution of symptomsEvolution of symptoms  April 2005 – ID visit:April 2005 – ID visit:  Now two persistent vaginal ulcersNow two persistent vaginal ulcers  Started on rifampin and minocycline for recurrent skinStarted on rifampin and minocycline for recurrent skin abscesses secondary to MRSAabscesses secondary to MRSA  Many courses of Valtrex to date without improvementMany courses of Valtrex to date without improvement  Patient presents to ER on multiple occasions 2005-Patient presents to ER on multiple occasions 2005- 2006, receives IV opiates, then discharged2006, receives IV opiates, then discharged
    11. 11. Gynecology Admission 2006Gynecology Admission 2006  October 2006:October 2006:  10/9: Presented to urgent care with genital ulcers infected10/9: Presented to urgent care with genital ulcers infected with E. coli and Klebsiella; CT with soft tissue thickening ofwith E. coli and Klebsiella; CT with soft tissue thickening of labia majora and minimal stranding around perirectal regionlabia majora and minimal stranding around perirectal region  10/20: ER with significant genital pain, fever, inability to eat10/20: ER with significant genital pain, fever, inability to eat due to oral sores, 30 lbs weight loss since 2003, and blurrydue to oral sores, 30 lbs weight loss since 2003, and blurry vision for a monthvision for a month  Given prior culture, initially treated with Zosyn andGiven prior culture, initially treated with Zosyn and fluconazolefluconazole  Awoke with a big black spot in the center of her vision,Awoke with a big black spot in the center of her vision, blurry peripheral vision, white floaters in her left eyeblurry peripheral vision, white floaters in her left eye
    12. 12. Past Medical HistoryPast Medical History  Polycystic ovarian syndrome s/p laparoscopyPolycystic ovarian syndrome s/p laparoscopy and ovarian cystectomyand ovarian cystectomy  History of drug abuseHistory of drug abuse  AsthmaAsthma  AnemiaAnemia  MigrainesMigraines
    13. 13. Medications, Allergies, Family &Medications, Allergies, Family & Social HistorySocial History  Medications: pHisoHex, lidocaine topically, Imitrex prnMedications: pHisoHex, lidocaine topically, Imitrex prn  Allergies: NKDAAllergies: NKDA  FH: No autoimmune disease; + lung CA, HTN, DM,FH: No autoimmune disease; + lung CA, HTN, DM, heart disease, EtOH abuse, drug addictionheart disease, EtOH abuse, drug addiction  SH: smokes 6-7 cigarettes/day, occ EtOH, no IVDU,SH: smokes 6-7 cigarettes/day, occ EtOH, no IVDU, last smoked cocaine/marijuana 2 weeks agolast smoked cocaine/marijuana 2 weeks ago
    14. 14. Physical ExaminationPhysical Examination  Tm 39.2, wt 44.9 kgTm 39.2, wt 44.9 kg  CachecticCachectic  Numerous open comedones and pitted scars on theNumerous open comedones and pitted scars on the faceface  Left lateral aspect of tongue, 1 cm oval erosion with aLeft lateral aspect of tongue, 1 cm oval erosion with a pseudomembrane overlying it and a slightly hyperemicpseudomembrane overlying it and a slightly hyperemic border.  Similar lesion on the left side of herborder.  Similar lesion on the left side of her tongue.  Two healing ulcers on the lower lip.tongue.  Two healing ulcers on the lower lip.
    15. 15. Physical ExaminationPhysical Examination  2/6 systolic murmur LLSB and apex2/6 systolic murmur LLSB and apexaxillaaxilla  +BS, soft, NT, ND, no hepatosplenomegaly+BS, soft, NT, ND, no hepatosplenomegaly  Faint hyperpigmented papules bilateral shins; noFaint hyperpigmented papules bilateral shins; no pathergy at blood draw sitespathergy at blood draw sites  Neck supple, no photophobia, CN/strength normalNeck supple, no photophobia, CN/strength normal  No synovitisNo synovitis
    16. 16. Physical ExaminationPhysical Examination www.rheumtext.com - Hochberg et al (eds)
    17. 17. Ophthalmic EvaluationOphthalmic Evaluation  10/22: Wilmer ER10/22: Wilmer ER  Concern for bilateral intermediate uveitis with possibleConcern for bilateral intermediate uveitis with possible macular infarction and macular edema in the right eye andmacular infarction and macular edema in the right eye and some vitreous hemorrhage in the left eyesome vitreous hemorrhage in the left eye  Started on solumedrol 1gm IV Q24h x 3 dosesStarted on solumedrol 1gm IV Q24h x 3 doses  10/23: Seen by an ophthalmology attending who noted10/23: Seen by an ophthalmology attending who noted only mild nonspecific findings of ocular inflammation;only mild nonspecific findings of ocular inflammation; fluoroscein angiogram not suggestive of retinalfluoroscein angiogram not suggestive of retinal vasculitis.vasculitis.
    18. 18. Gynecologic, GI, ID, and ImagingGynecologic, GI, ID, and Imaging EvaluationEvaluation  10/24: OR for wound debridement, and right vulvar and perianal10/24: OR for wound debridement, and right vulvar and perianal biopsybiopsy  Cytopathology: squamous metaplasiaCytopathology: squamous metaplasia  Right labial and perianal skin biopsies: diffuse lymphohistiocyticRight labial and perianal skin biopsies: diffuse lymphohistiocytic inflammation and ulcer. Could be consistent with Behçet's disease.inflammation and ulcer. Could be consistent with Behçet's disease.  No hematochezia or diarrhea.No hematochezia or diarrhea. EGD and colonoscopy notable only for mild gastritis.  EGD and colonoscopy notable only for mild gastritis.    ID concerned re: histoplasmosis, LGV, HIV, malignancy; ID workupID concerned re: histoplasmosis, LGV, HIV, malignancy; ID workup negativenegative  History of migraines. Unremarkable MRI of the brain.History of migraines. Unremarkable MRI of the brain.
    19. 19. Evaluation ofEvaluation of MucocutaneousMucocutaneous UlcerationUlceration
    20. 20. BehBehçet’s Diseaseçet’s Disease  Multisystem inflammatory disorderMultisystem inflammatory disorder  Described in 1937 by Hulusi BehDescribed in 1937 by Hulusi Behçet as triad ofçet as triad of oral ulcers/genital ulcers/uveitisoral ulcers/genital ulcers/uveitis  Increased prevalence along the ancient “SilkIncreased prevalence along the ancient “Silk Road” in Asia/Middle East:Road” in Asia/Middle East:  Turkey: 80-370/100,000Turkey: 80-370/100,000  U.S.: 0.12-0.33/100,000U.S.: 0.12-0.33/100,000  Associated with HLA-B51 in all ethnic groupsAssociated with HLA-B51 in all ethnic groups Sakane, T., et. al. N Engl J Med. 1999 Oct 21;341(17):1284-91.
    21. 21. Diagnosing BehDiagnosing Behçet’s: Internationalçet’s: International Study Group (ISG) CriteriaStudy Group (ISG) Criteria  Recurrent oral ulcerationRecurrent oral ulceration PLUS 2 of the following:PLUS 2 of the following:  Recurrent genital ulcerationRecurrent genital ulceration  Eye lesionsEye lesions  Skin lesionsSkin lesions  PositivePositive pathergypathergy test at 24-48test at 24-48oo  Anterior uveitis, posterior uveitis, or cells in theAnterior uveitis, posterior uveitis, or cells in the vitreous on slit-lamp examination; or retinalvitreous on slit-lamp examination; or retinal vasculitis detected by an ophthalmologistvasculitis detected by an ophthalmologist  Erythema nodosum, pseudofolliculitis, orErythema nodosum, pseudofolliculitis, or papulopustular lesions; or acneiform nodules in apapulopustular lesions; or acneiform nodules in a postadolescent not receiving corticosteroidspostadolescent not receiving corticosteroids  Minor aphthous, major aphthous, orMinor aphthous, major aphthous, or herpetiform ulcers observed by theherpetiform ulcers observed by the physician or patient recurring at least 3physician or patient recurring at least 3 times in one 12-month periodtimes in one 12-month period In the absence of other clinical explanations, patients must have:In the absence of other clinical explanations, patients must have: International Study Group for Behçet's Disease. Lancet. 1990 May 5;335(8697):1078-80.
    22. 22. Performance of ISG CriteriaPerformance of ISG Criteria  Criteria derived by consensus from 914 patientsCriteria derived by consensus from 914 patients with Behwith Behççet’s from 12 centers in 7 countrieset’s from 12 centers in 7 countries  Validated in a large cohort of 302 patients withValidated in a large cohort of 302 patients with B.D. and 438 patients with other diagnosesB.D. and 438 patients with other diagnoses (including IBD)(including IBD)  98% sensitivity and 99% specificity98% sensitivity and 99% specificity International Study Group for Behçet's Disease. Lancet. 1990 May 5;335(8697):1078-80. Tunc R et al. Clin Exp Rheumatol 19; 2001 S45-7.
    23. 23. Frequency of the ClinicalFrequency of the Clinical Manifestations of Behçet’s SyndromeManifestations of Behçet’s Syndrome and the ISG Diagnostic Criteriaand the ISG Diagnostic Criteria www.rheumtext.com – Hochberg et al (eds)
    24. 24. Complex AphthosisComplex Aphthosis  Required for diagnosis:Required for diagnosis:  Near constant presence of multiple oral ulcers (>3)Near constant presence of multiple oral ulcers (>3) oror  Recurrent oral and genital ulcersRecurrent oral and genital ulcers andand  Exclusion of BehExclusion of Behççet’set’s  Can be 1Can be 1° (idiopathic) or 2°° (idiopathic) or 2°  Major 2° causes: IBD, HIV, celiac disease, cyclicMajor 2° causes: IBD, HIV, celiac disease, cyclic neutropenia, agranulocytosis, vitamin deficiencies (iron,neutropenia, agranulocytosis, vitamin deficiencies (iron, folate, zinc, B1, B2, B6, B12),folate, zinc, B1, B2, B6, B12), FAPA (fever, aphthous stomatitis, pharyngitis, adenitis)  Possible implication of food allergies: cows’ milk,Possible implication of food allergies: cows’ milk, gluten, food dyes, and preservativesgluten, food dyes, and preservatives Letsinger, J.A. et. al. J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):500-8. Ghate, J.V. et. al. J Am Acad Dermatol. 1999 Jan; 40 (1): 1-18.
    25. 25. The Wake Forest ExperienceThe Wake Forest Experience 1995-20011995-2001 81 patients referred for evaluation of Behçet’s 10 (12%) 17 (21%) Behçet’s Other: simple recurrent aphthous stomatitis or non-aphthous oral disease 54 (67%) with complex aphthosis 2° 12 (22%) 1° Letsinger, J.A. et. al. J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):500-8. 42 (78%)
    26. 26. The Wake Forest ExperienceThe Wake Forest Experience 1995-20011995-2001  10/12 with 210/12 with 2° aphthosis had IBD° aphthosis had IBD  13/42 with 1° idiopathic disease had concurrent13/42 with 1° idiopathic disease had concurrent genital ulcerationsgenital ulcerations  Over 6 years of f/u, none of the patients with 1°Over 6 years of f/u, none of the patients with 1° aphthosis developed Behçet’saphthosis developed Behçet’s  Topical steroids used in 39/42; all receivedTopical steroids used in 39/42; all received systemic Rx initially with colchicine, dapsone,systemic Rx initially with colchicine, dapsone, thalidomidethalidomide Letsinger, J.A. et. al. J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):500-8.
    27. 27. Diagnostic ApproachDiagnostic Approach Letsinger, J.A. et. al. J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):500-8.
    28. 28. Differential Diagnosis of Behçet’sDifferential Diagnosis of Behçet’s SyndromeSyndrome
    29. 29. Vulvar Ulceration in Crohn’s DiseaseVulvar Ulceration in Crohn’s Disease  Many case reports of Crohn’sMany case reports of Crohn’s disease of the vulvadisease of the vulva  In one case report, GIIn one case report, GI symptoms developed 3 yearssymptoms developed 3 years after biopsy proven Crohn’safter biopsy proven Crohn’s of the vulvaof the vulva Bhaduri, S. et. al. Int J STD AIDS. 2005 Jul;16(7):512-4 Feller, E.R. et. al. Am Fam Physician. 2001 Nov;64(10):1725-8  GynecologicGynecologic Complications inComplications in Crohn’sCrohn’s
    30. 30. Systemic MedicalSystemic Medical Management ofManagement of Mucocutaneous Ulcers inMucocutaneous Ulcers in Behçet’sBehçet’s
    31. 31. CorticosteroidsCorticosteroids  86 patients with active Behçet’s and at least one genital ulcer occurring within the preceding 6 months  Exclusions: immunosuppressive agents and corticosteroids 5 mg/day within the preceding 1 month, severe organ involvement, diabetes mellitus, active infection, peptic ulcer, hypertension or pregnancy.  Continued their previous treatment with colchicine, low-dose ASA, amitriptyline, acetaminophen or NSAIDS. Topical treatment and systemic thalidomide permitted for oral and genital ulcers Mat, C., et. al. Rheumatology (Oxford). 2006 Mar;45(3):348-52.
    32. 32. CorticosteroidsCorticosteroids  Randomized to 40mg methylprednisolone IM or placebo saline injections Q3 weeks for 27 weeks  Primary Outcome: Difference in the mean number of genital ulcers between the two arms  Secondary Outcomes: Differences in the mean numbers of other mucocutaneous lesions and attacks of arthritis Mat, C., et. al. Rheumatology (Oxford). 2006 Mar;45(3):348-52.
    33. 33. Results & Primary OutcomesResults & Primary Outcomes  76 patients (88%) completed the treatment  One male from each groupOne male from each group withdrawn from the trial becausewithdrawn from the trial because of the development of eye diseaseof the development of eye disease  One female patient from eachOne female patient from each group treated with a short coursegroup treated with a short course of thalidomide, one for genital andof thalidomide, one for genital and one for severe oral ulceration.one for severe oral ulceration.  No significant differences in the mean number of genital and oral ulcers, or folliculitis between groups.  Mean half-life of intramuscularMean half-life of intramuscular methylprednisolone ~ 139 h (rangemethylprednisolone ~ 139 h (range 56–886 h)56–886 h)  May have underdosed or givenMay have underdosed or given steroid too infrequently.steroid too infrequently.  Skin infection might play a role inSkin infection might play a role in the pathogenesis of some of thethe pathogenesis of some of the manifestations of BSmanifestations of BS Mat, C., et. al. Rheumatology (Oxford). 2006 Mar;45(3):348-52. Barnes CG. Rheumatology (Oxford). 2006 Mar;45(3):245-7.
    34. 34. Erythema Nodosum andErythema Nodosum and CorticosteroidsCorticosteroids  Clinical characteristics at baseline similar in the 2 arms except that the steroid arm had significantly fewer patients with a history of erythema nodosum [31% vs 61%, P=0.004].  Disappearance of a significance difference between treatment and placebo groups with cessation of therapy suggests that the effect of corticosteroids on erythema nodosum among females was real. Mat, C., et. al. Rheumatology (Oxford). 2006 Mar;45(3):348-52.
    35. 35. ColchicineColchicine  116 patients with Behçet’s (60 M/56 F) with active116 patients with Behçet’s (60 M/56 F) with active mucocutaneous disease (at least 3 episodes in last 6 months)mucocutaneous disease (at least 3 episodes in last 6 months)  Exclusions: eye or major organ involvement; colchicine,Exclusions: eye or major organ involvement; colchicine, steroid or othersteroid or other immunosuppressive therapy within the preceding 6 months  Randomized to placebo or colchicine (1–2mg/day, adjustedRandomized to placebo or colchicine (1–2mg/day, adjusted to body weight) in a double-blind trial for 2 yearsto body weight) in a double-blind trial for 2 years  Complete response: sustained absence of any lesionsComplete response: sustained absence of any lesions (ulcers, EN, follicular lesions) and arthritis during treatment(ulcers, EN, follicular lesions) and arthritis during treatment Yurdakul, S., et. al. Arthritis Rheum. 2001 Nov;44(11):2686-92.
    36. 36. ColchicineColchicine  Secondary outcome measure: Difference in theSecondary outcome measure: Difference in the number of mucocutaneous lesions or arthriticnumber of mucocutaneous lesions or arthritic joints between the active drug and placebojoints between the active drug and placebo  Women and men were analyzed separately.Women and men were analyzed separately.  Eighty-four patients (72%; 45 male, 39 female)Eighty-four patients (72%; 45 male, 39 female) completed the 24-month study.completed the 24-month study. Yurdakul, S., et. al. Arthritis Rheum. 2001 Nov;44(11):2686-92.
    37. 37. Colchicine ResultsColchicine Results • Efficacy not the same between males and females • Colchicine clearly effective for arthritis in both sexes • Beneficial effects of colchicine on erythema nodosum and genital lesions seen only among women. • Prior studies show men with more severe disease course Yurdakul, S., et. al. Arthritis Rheum. 2001 Nov;44(11):2686-92.
    38. 38. LevamisoleLevamisole  Open trial of 11 (3M, 8F) patients: 2 with completeOpen trial of 11 (3M, 8F) patients: 2 with complete Behçet’s by Japanese criteria, 8 with incomplete, 1 suspectedBehçet’s by Japanese criteria, 8 with incomplete, 1 suspected  Treated with varying doses of levamisole, ranging fromTreated with varying doses of levamisole, ranging from 150mg weekly – 150mg TIW150mg weekly – 150mg TIW  All 11 with active buccal ulcerations; 9 improved withAll 11 with active buccal ulcerations; 9 improved with therapy (4 complete and 5 partial)therapy (4 complete and 5 partial)  Flares occurred with drug interruption in 3 and improvedFlares occurred with drug interruption in 3 and improved with reinitiation in 2with reinitiation in 2 De Merieux, P., et. al. Arthritis Rheum. 1981 Jan;24(1):64-70.
    39. 39. MethotrexateMethotrexate  Report of 2 patients with Behçet’s and active mucocutaneousReport of 2 patients with Behçet’s and active mucocutaneous disease (cutaneous pustular vasculitis, pyoderma gangrenosum-disease (cutaneous pustular vasculitis, pyoderma gangrenosum- like lesions, oral and genital aphthae)like lesions, oral and genital aphthae)  Failure of multiple other agents including NSAIDs, colchicine,Failure of multiple other agents including NSAIDs, colchicine, intralesional steroid, dapsone, azathioprine and chlorambucilintralesional steroid, dapsone, azathioprine and chlorambucil  Resolution of disease at 3 weeks and 2 months withResolution of disease at 3 weeks and 2 months with methotrexate 15mg and 20mg Qweek, respectivelymethotrexate 15mg and 20mg Qweek, respectively  Oral corticosteroids discontinuedOral corticosteroids discontinued Jorizzo, J.L., et. al. J Am Acad Dermatol. 1991; 24:973-8.
    40. 40. ThalidomideThalidomide  Randomized, double-blind, placebo-controlled trial inRandomized, double-blind, placebo-controlled trial in specialized Behçet’s clinic in Turkey from 1993-1996.specialized Behçet’s clinic in Turkey from 1993-1996.  96 male patients with Behçet’s with active96 male patients with Behçet’s with active mucocutaneous lesions but without major organmucocutaneous lesions but without major organ involvement, previous use of immunosuppressiveinvolvement, previous use of immunosuppressive therapy, or clinical neuropathy.therapy, or clinical neuropathy.  Thalidomide, 100 mg/d or 300 mg/d, or placebo for 24Thalidomide, 100 mg/d or 300 mg/d, or placebo for 24 weeks. Includes f/u 4 weeks after treatment ended.weeks. Includes f/u 4 weeks after treatment ended. Hamuryudan, V. et. al. Ann Intern Med 1998;128:443-450
    41. 41. ThalidomideThalidomide  For data collection, only the number of new lesions wasFor data collection, only the number of new lesions was considered.considered.  Complete response: Sustained absence of any oral andComplete response: Sustained absence of any oral and genital ulceration during treatmentgenital ulceration during treatment  Also measured changes in the number ofAlso measured changes in the number of mucocutaneous lesions.mucocutaneous lesions.  Polyneuropathy developed in 1 in the 100-mg/d groupPolyneuropathy developed in 1 in the 100-mg/d group and 3 in the 300-mg/d group; 3 of these diagnosedand 3 in the 300-mg/d group; 3 of these diagnosed after trial had ended.after trial had ended. Hamuryudan, V. et. al. Ann Intern Med 1998;128:443-450
    42. 42. Complete Response:  Thalidomide, 100 mg/d: 2/32 (6%)  Thalidomide, 300 mg/d: 5/31 (16%)  Placebo: 0/32 Most treatment failures occurred within the first 4 weeks. Time-dependent distribution of patients with sustained absence of oral or genital ulcers Hamuryudan, V. et. al. Ann Intern Med 1998;128:443-450
    43. 43. Diamonds = placebo; squares = 100-mg/d thalidomide; triangles = 300-mg/d thalidomide. Mean differences in mucocutaneous lesions at admission (week 0), during treatment (weeks 4-24), and 4 weeks after treatment (week 28) Hamuryudan, V. et. al. Ann Intern Med 1998;128:443-450 Dose independent effect persists during treatment but diminishes rapidly afterwards. P < 0.001 P < 0.001 P= 0.008 Both doses increase # of EN lesions P= 0.03
    44. 44. AzathioprineAzathioprine  No significant data looking at effectiveness ofNo significant data looking at effectiveness of azathioprine in mucocutaneous ulceration of Behçet’sazathioprine in mucocutaneous ulceration of Behçet’s diseasedisease  2-year randomized, placebo-controlled, double-blind2-year randomized, placebo-controlled, double-blind trial of azathioprine (2.5 mg/kg/d) in Turkish men withtrial of azathioprine (2.5 mg/kg/d) in Turkish men with Behçet's syndrome without eye disease (group 1; n =Behçet's syndrome without eye disease (group 1; n = 25) or with eye disease (group 2; n = 48)25) or with eye disease (group 2; n = 48)  Exclusions: irreversible bilateral eye disease,Exclusions: irreversible bilateral eye disease, immunosuppressive therapy in the last 3 months,immunosuppressive therapy in the last 3 months, steroid therapy in the last monthsteroid therapy in the last month Yazici, H., et al. N Engl J Med. 1990 Feb 1;322(5):281-5.
    45. 45. AzathioprineAzathioprine  Corticosteroid treatment available to allCorticosteroid treatment available to all  6 patients on placebo withdrawn from study because of6 patients on placebo withdrawn from study because of severe eye disease (P < 0.001)severe eye disease (P < 0.001)  Azathioprine superior to placebo in the prevention ofAzathioprine superior to placebo in the prevention of new eye disease in group 1 (1 vs. 8 patients; P < 0.01)new eye disease in group 1 (1 vs. 8 patients; P < 0.01) and in group 2 among the 14 patients who at entry hadand in group 2 among the 14 patients who at entry had disease in only one eye (P < 0.001).disease in only one eye (P < 0.001).  Fewer episodes of hypopyon uveitis (1 vs. 15; P <Fewer episodes of hypopyon uveitis (1 vs. 15; P < 0.001) among group 2 patients who took azathioprine.0.001) among group 2 patients who took azathioprine. Yazici, H., et al. N Engl J Med. 1990 Feb 1;322(5):281-5.
    46. 46. Extraocular ManifestationsExtraocular Manifestations ManifestationManifestation Ever PresentEver Present Present atPresent at Initial VisitInitial Visit New DuringNew During TrialTrial Present at 24Present at 24 MonthsMonths AZAAZA (N = 37)(N = 37) PlaceboPlacebo (N = 36)(N = 36) AZAAZA (N = 37)(N = 37) PlaceboPlacebo (N = 36)(N = 36) AZAAZA PlaceboPlacebo AZAAZA (N = 34)(N = 34) PlaceboPlacebo (N = 23)(N = 23) number of patients (percent) Oral ulcerationOral ulceration 3737 (100)(100) 36 (100)36 (100) 16 (43)16 (43) 21 (58)21 (58) 1111 (52)(52) 7 (47)7 (47) 4 (12)4 (12) 8 (35)8 (35) GenitalGenital ulcerationulceration 32 (86)32 (86) 29 (80)29 (80) 6 (16)6 (16) 4 (11)4 (11) 3 (10)3 (10) 12 (38)12 (38) 1 (3)1 (3) 8 (13)8 (13) ErythemaErythema nodosumnodosum 20 (54)20 (54) 11 (31)11 (31) 5 (14)5 (14) 3 (8)3 (8) 6 (19)6 (19) 7 (21)7 (21) 0 (0)0 (0) 0 (0)0 (0) PapulopustularPapulopustular lesionslesions 28 (76)28 (76) 29 (81)29 (81) 23 (62)23 (62) 23 (64)23 (64) 1111 (79)(79) 11 (85)11 (85) 27 (79)27 (79) 17 (74)17 (74) Yazici, H., et al. N Engl J Med. 1990 Feb 1;322(5):281-5. • AZA may not prevent development of new oral ulcers but may improve healingAZA may not prevent development of new oral ulcers but may improve healing • Among those initially without GU, 3 in AZA vs 12 in placebo developed GUAmong those initially without GU, 3 in AZA vs 12 in placebo developed GU • No effect on papulopustular lesionsNo effect on papulopustular lesions
    47. 47. CyclosporineCyclosporine  96 patients, age ≥ 15, with complete or incomplete96 patients, age ≥ 15, with complete or incomplete Behçet’s as defined by the Japan Behçet’s DiseaseBehçet’s as defined by the Japan Behçet’s Disease Research Committee 1982 Criteria enrolledResearch Committee 1982 Criteria enrolled  Visual acuity ≤ 20/40, at least 2 ocular attacks duringVisual acuity ≤ 20/40, at least 2 ocular attacks during 16 weeks before the study16 weeks before the study  Randomized to cyclosporine 10mg/kg po daily andRandomized to cyclosporine 10mg/kg po daily and colchicine 1mg daily for 16 weekscolchicine 1mg daily for 16 weeks  Dose reduced or treatment discontinued if side effectsDose reduced or treatment discontinued if side effects Masuda, K., et. al. Lancet. 1989 May 20;1(8647):1093-6
    48. 48. CyclosporineCyclosporine  Oral aphthous ulcers, dermal lesions, and genital ulcersOral aphthous ulcers, dermal lesions, and genital ulcers were classified into 4 grades (0-3) based on frequencywere classified into 4 grades (0-3) based on frequency and number of lesionsand number of lesions  Cyclosporine alleviated oral aphthous ulcers in 33Cyclosporine alleviated oral aphthous ulcers in 33 (70%); colchicine in 10 (20%) – p<0.001(70%); colchicine in 10 (20%) – p<0.001  Dermal lesions alleviated in 40% of cyclosporine-Dermal lesions alleviated in 40% of cyclosporine- treated patients vs 15% of colchicine-treated – p<0.01treated patients vs 15% of colchicine-treated – p<0.01  Hirsutism and renal dysfunction especially common inHirsutism and renal dysfunction especially common in cyclosporine groupcyclosporine group Masuda, K., et. al. Lancet. 1989 May 20;1(8647):1093-6
    49. 49. CyclosporineCyclosporine  Longer term study in 36 patients with complete orLonger term study in 36 patients with complete or incomplete Behçet’s who had ocular lesions and did notincomplete Behçet’s who had ocular lesions and did not respond well to prior treatmentsrespond well to prior treatments  Cyclosporine 10mg/kg daily; trough levels followed,Cyclosporine 10mg/kg daily; trough levels followed, goal maintenance dose 6-8mg/kg/dgoal maintenance dose 6-8mg/kg/d  Mean duration of therapy 44 weeksMean duration of therapy 44 weeks  Alleviated oral and genital ulcers by 2 grades or moreAlleviated oral and genital ulcers by 2 grades or more Masuda, K., et. al. Lancet. 1989 May 20;1(8647):1093-6
    50. 50. CyclosporineCyclosporine  30 Behçet’s patients with pathergy and active30 Behçet’s patients with pathergy and active mucocutaneous disease studiedmucocutaneous disease studied  Treated with cyclosporine 5mg/kg/d; dose adjustedTreated with cyclosporine 5mg/kg/d; dose adjusted to 2.5mg/kg/d if Cr exceeded 30% of baseline levelto 2.5mg/kg/d if Cr exceeded 30% of baseline level  6 patients excluded for irregular drug use; 19 men6 patients excluded for irregular drug use; 19 men and 5 women were treated for >6 monthsand 5 women were treated for >6 months Avci, O. et. al. J Am Acad Dermatol 1997;36:796–7.
    51. 51. CyclosporineCyclosporine  Oral ulcers in 24/24 pretreatmentOral ulcers in 24/24 pretreatment  Symptom free intervals increased from 2.7 to 4.9Symptom free intervals increased from 2.7 to 4.9 weeksweeks  Average number of oral ulcers decreased from 4.6 toAverage number of oral ulcers decreased from 4.6 to 1.71.7  Average size decreased from 5.7 to 3.6mmAverage size decreased from 5.7 to 3.6mm  25% had no oral ulcers during treatment25% had no oral ulcers during treatment  Genital ulcers in 21/24 pretreatmentGenital ulcers in 21/24 pretreatment  80% had no genital lesions during therapy; 2 patients80% had no genital lesions during therapy; 2 patients worsenedworsened Avci, O. et. al. J Am Acad Dermatol 1997;36:796–7.
    52. 52. InterferonInterferon αα-2a-2a  50 patients with BD by ISG criteria (19 females, 31 males)50 patients with BD by ISG criteria (19 females, 31 males)  Exclusion criteria: hepatic, renal, CV, infectious or otherExclusion criteria: hepatic, renal, CV, infectious or other autoimmune disease; coagulopathy; systemic therapy for last 12autoimmune disease; coagulopathy; systemic therapy for last 12 weeks or topical therapy for last 4 weeks; pregnant or lactating;weeks or topical therapy for last 4 weeks; pregnant or lactating; active cerebral or retinal vasculitis; irreversible bilateral eyeactive cerebral or retinal vasculitis; irreversible bilateral eye diseasedisease  3 month period of observation where all attacks were recorded3 month period of observation where all attacks were recorded  Randomized to IFN alpha-2a (6 x 10Randomized to IFN alpha-2a (6 x 1066 IU) or placebo SQ TIWIU) or placebo SQ TIW  Followed weekly until 3 months post-treatmentFollowed weekly until 3 months post-treatment Alpsoy, E., et. al. Arch Dermatol 2002;138:467–71.
    53. 53. InterferonInterferon αα-2a-2a  Complete response:Complete response:  disappearance of all signs and symptomsdisappearance of all signs and symptoms  IFN group 2/23 CRIFN group 2/23 CR  Partial response:Partial response:  > 50% decrease in frequency, duration, and> 50% decrease in frequency, duration, and severity of pain for OU and GU and/orseverity of pain for OU and GU and/or  a decrease in the severity and frequency ofa decrease in the severity and frequency of attacks for ocular involvementattacks for ocular involvement  13/23 IFN, 3/21 placebo13/23 IFN, 3/21 placebo Alpsoy, E., et. al. Arch Dermatol 2002;138:467–71.
    54. 54. InterferonInterferon αα-2a-2a  Stable disease:Stable disease:  < 50% change in clinical signs and< 50% change in clinical signs and symptomssymptoms  4/23 IFN, 3/21 placebo4/23 IFN, 3/21 placebo  No effect or deterioration:No effect or deterioration:  ineffectiveness or worsening of clinicalineffectiveness or worsening of clinical signs and symptomssigns and symptoms  4/23 IFN, 15/21 placebo4/23 IFN, 15/21 placebo Alpsoy, E., et. al. Arch Dermatol 2002;138:467–71.
    55. 55. InterferonInterferon αα-2a-2a  Six patients (2 in IFN group and 4 in placebo) did not complete theSix patients (2 in IFN group and 4 in placebo) did not complete the studystudy  severe eye disease in 3 (1 in IFN, 2 in placebo)severe eye disease in 3 (1 in IFN, 2 in placebo)  progressive mucocutaneous symptoms (1 in IFN)progressive mucocutaneous symptoms (1 in IFN)  new eye disease and mucocutaneous symptoms (1 in placebo)new eye disease and mucocutaneous symptoms (1 in placebo)  progressive mucocutaneous and articular symptoms (1 in placebo)progressive mucocutaneous and articular symptoms (1 in placebo)  IFN significantly decreasedIFN significantly decreased  the duration and pain of oral ulcers rapidlythe duration and pain of oral ulcers rapidly  the frequency of genital ulcers and papulopustular lesionsthe frequency of genital ulcers and papulopustular lesions  Frequency and duration of EN and thrombophlebitis decreased butFrequency and duration of EN and thrombophlebitis decreased but not statistically significantnot statistically significant  All symptoms returned to pretreatment levels in posttreatment follow-All symptoms returned to pretreatment levels in posttreatment follow- up periodup period Alpsoy, E., et. al. Arch Dermatol 2002;138:467–71.
    56. 56. EtanerceptEtanercept  Presence of T cell, monocyte, and macrophage infiltration and the expression of IFN-γ and IL-12 suggest a Th1-type immune response in the pathogenesis of pathergy.  Skin hyperreactivity in BD can also be induced by the intradermal injection of monosodium urate (MSU) crystals.  Positive MSU test: defined as a persistent area of erythema at the injection site at 48 h. Sensitivity of 61– 78% and specificity of 94–100%. Melikoglu, M., et. al. J Rheumatol. 2005 Jan;32(1):98-105.
    57. 57. EtanerceptEtanercept  Double blind, placebo controlled trial to evaluate the effect of etanercept on pathergy and MSU reactions along with the mucocutaneous manifestations in patients with BD  Inclusion criteria: male sex; positive pathergy and a MSU test; at least one of the following within the preceding 3 months of study entry: (a) one episode of oral ulcer, (b) genital ulcer, (c) nodular lesion (erythema nodosum or superficial thrombophlebitis), (d) a swollen joint.  Exclusion criteria: serious organ involvement, infection, history of TB, use of etanercept during the 4 weeks prior to study entry, ALT and AST 2 times above the normal limits, a Hct < 28%, WBC count < 4000/mm3, platelet count < 140,000/mm3, and a Cr of > 1.9 mg/dl. Melikoglu, M., et. al. J Rheumatol. 2005 Jan;32(1):98-105.
    58. 58. EtanerceptEtanercept  40 patients randomized to etanercept 25mg BIW or placebo for 4 weeks  Drug washout: 18 patients who were using colchicine (11 in the etanercept and 7 in the placebo arms) and 5 patients who were using azathioprine (all in the placebo arm) due to resistant mucocutaneous lesions, stopped their medications for a 4 week washout period before entering the trial  2 patients in the etanercept arm (one with a recent exacerbation of DVT and one with painful arthritis) and one in the placebo arm (again with a recent exacerbation of DVT) did not undergo this washout period  Pathergy and MSU tests were performed at the initial visit, weeks 1 and 4, and at the third month after the trial ended Melikoglu, M., et. al. J Rheumatol. 2005 Jan;32(1):98-105.
    59. 59. EtanerceptEtanercept • Statistically significant improvement in oral ulcers and nodular lesions by week 1, but benefit not sustained at 3 months. • No improvement in genital ulcers, pathergy, MSU test. • Lack of effect on genital ulcers may be due to small sample size and the relative infrequency of genital ulcerations Melikoglu, M., et. al. J Rheumatol. 2005 Jan;32(1):98-105.
    60. 60. Response to Infliximab afterResponse to Infliximab after Etanercept FailureEtanercept Failure  38-yr-old Caucasian woman with Behçet’s: recurrent orogenital ulceration, arthralgia, severe iritis, positive pathergy test, erythema nodosum.  Severe ulceration of the nasopharynx, labia and vulva with areas of scarring.  No benefit with topical triamcinolone, colchicine, cyclosporine, pulsed high-dose IV methylprednisolone, chlorambucil and thalidomide  No improvement in ulceration after 3 mo trial etanercept 25 mg SQ BIW Estrach, C., et. al. Rheumatology (Oxford). 2002 Oct;41(10):1213-4.
    61. 61. Response to Infliximab afterResponse to Infliximab after Etanercept FailureEtanercept Failure  Switched to infliximab 3 mg/kg at 0 and 2 weeks and then at Q8 weeks, together with methotrexate 7.5 mg orally Qweek  After the first infusion  Resolution of orogenital ulceration and erythema nodosum  1 yr later, continued remission on therapy with infliximab. Estrach, C., et. al. Rheumatology (Oxford). 2002 Oct;41(10):1213-4.
    62. 62. Infliximab for Recurrent OrogenitalInfliximab for Recurrent Orogenital Ulceration in Behçet’sUlceration in Behçet’s  Case report of woman with 10 years of persistentCase report of woman with 10 years of persistent ulceration unresponsive to therapy with oralulceration unresponsive to therapy with oral thalidomide, dapsone, azathioprine, colchicine andthalidomide, dapsone, azathioprine, colchicine and cyclosporinecyclosporine  Trial of infliximab 5mg/kg at weeks 0, 2, and 6Trial of infliximab 5mg/kg at weeks 0, 2, and 6  Marked decrease in number of ulcers after firstMarked decrease in number of ulcers after first infusion; no ulcers after 3infusion; no ulcers after 3rdrd infusion with sustainedinfusion with sustained responseresponse Robertson, L.P. et. al. Rheumatology (Oxford). 2001 Apr;40(4):473-4.
    63. 63. InfliximabInfliximab  40 year old man diagnosed with PAN in 1986 due to40 year old man diagnosed with PAN in 1986 due to painful nodules and foot ulcers; deep skin biopsy withpainful nodules and foot ulcers; deep skin biopsy with obliteration of the vascular lumen with necrosis andobliteration of the vascular lumen with necrosis and infiltration of lymphocytes in the vascular wallinfiltration of lymphocytes in the vascular wall  Persistent disease activity on prednisone 40 mg daily;Persistent disease activity on prednisone 40 mg daily; azathioprine (150 mg/day) and cyclophosphamide (100azathioprine (150 mg/day) and cyclophosphamide (100 mg/day)mg/day)  Steroid dependent; no remission withSteroid dependent; no remission with cyclophosphamide pulse treatment or thalidomidecyclophosphamide pulse treatment or thalidomide Goossens PH, et. al.Ann Rheum Dis. 2001 Jun;60(6):637.
    64. 64. InfliximabInfliximab  September 1999: oral, anal, and penile ulcers; treatedSeptember 1999: oral, anal, and penile ulcers; treated with prednisone 15 mg/day and methotrexate 15with prednisone 15 mg/day and methotrexate 15 mg/week. Continued foot ulcers and now retinalmg/week. Continued foot ulcers and now retinal vasculitisvasculitis  Diagnosed with Behçet’s and infliximab 10 mg/kgDiagnosed with Behçet’s and infliximab 10 mg/kg given at 0 and 4 weeksgiven at 0 and 4 weeks  No ulcers at the time of the second infusion. RemissionNo ulcers at the time of the second infusion. Remission 12 months after last infusion12 months after last infusion Goossens PH, et. al.Ann Rheum Dis. 2001 Jun;60(6):637.
    65. 65. Infliximab for Recurrent OrogenitalInfliximab for Recurrent Orogenital Ulceration in Behçet’sUlceration in Behçet’s  39 year-old woman with Behçet’s39 year-old woman with Behçet’s  Worsening orogenital ulceration, recurrent large pustules,Worsening orogenital ulceration, recurrent large pustules, progressive chest pain, breathlessness, arthralgia, influenza-likeprogressive chest pain, breathlessness, arthralgia, influenza-like symptoms, myalgia, uveitis, paresthesias, and severe chronicsymptoms, myalgia, uveitis, paresthesias, and severe chronic diarrhea.diarrhea.  Age 25–39: Trials of colchicine, prednisolone 30–60 mg daily,Age 25–39: Trials of colchicine, prednisolone 30–60 mg daily, azathioprine 50 mg TID, sulfasalazine 500 mg TID, leflunomideazathioprine 50 mg TID, sulfasalazine 500 mg TID, leflunomide 10 mg daily, cyclosporine 100 mg BID, methotrexate 15 mg10 mg daily, cyclosporine 100 mg BID, methotrexate 15 mg weekly, thalidomide 100 mg QHS.weekly, thalidomide 100 mg QHS.  Withdrew thalidomide due to peripheral neuropathyWithdrew thalidomide due to peripheral neuropathy  severesevere rebound of oropharyngeal and genital ulceration.rebound of oropharyngeal and genital ulceration. Connolly, M. et. al. Br J Dermatol. 2005 Nov;153(5):1073-5.
    66. 66. Infliximab for Recurrent OrogenitalInfliximab for Recurrent Orogenital Ulceration in Behçet’sUlceration in Behçet’s  Infliximab 3 mg/kg at weeks 0, 2, 6, 12, and then Q8 weeks;Infliximab 3 mg/kg at weeks 0, 2, 6, 12, and then Q8 weeks; methotrexate 15 mg weekly continuedmethotrexate 15 mg weekly continued  Within 2 days of starting infliximab, all ulceration had begun toWithin 2 days of starting infliximab, all ulceration had begun to heal.heal.  No relapse of ulceration after 12 months of therapy.No relapse of ulceration after 12 months of therapy. Connolly, M. et. al. Br J Dermatol. 2005 Nov;153(5):1073-5.
    67. 67.  Randomized, multicenter, double-blind, placebo-Randomized, multicenter, double-blind, placebo- controlled trial of infliximab for the treatment ofcontrolled trial of infliximab for the treatment of fistulas in Crohn’sfistulas in Crohn’s  94 adults with draining abdominal or perianal fistulas94 adults with draining abdominal or perianal fistulas for at least 3 monthsfor at least 3 months  Randomly assigned to placebo (31 patients), 5 mg/kg ofRandomly assigned to placebo (31 patients), 5 mg/kg of infliximab (31 patients), or 10 mg/kg of infliximab (32infliximab (31 patients), or 10 mg/kg of infliximab (32 patients) IV at weeks 0, 2, and 6.patients) IV at weeks 0, 2, and 6. Of all these agents, why chooseOf all these agents, why choose infliximab?infliximab? Present, D.H. et. al. N Engl J Med. 1999; 340(18):1398-405
    68. 68.  Primary end point: ≥ 50% reduction in the number ofPrimary end point: ≥ 50% reduction in the number of draining fistulas observed at two or more consecutivedraining fistulas observed at two or more consecutive visits.visits.  68% of 5 mg/kg group and 56% of 10 mg/kg group,68% of 5 mg/kg group and 56% of 10 mg/kg group, compared with 26% of placebo group (P=0.002 andcompared with 26% of placebo group (P=0.002 and P=0.02, respectively).P=0.02, respectively).  Secondary endpoint: closure of all fistulas.Secondary endpoint: closure of all fistulas.  55% of 5 mg/kg group and 38% of 10 mg/kg group,55% of 5 mg/kg group and 38% of 10 mg/kg group, compared with 13 % of placebo (P=0.001 andcompared with 13 % of placebo (P=0.001 and P=0.04).P=0.04).  Median length of time during which the fistulasMedian length of time during which the fistulas remained closed was three months.remained closed was three months. Of all these agents, why chooseOf all these agents, why choose infliximab?infliximab? Present, D.H. et. al. N Engl J Med. 1999; 340(18):1398-405
    69. 69. Infliximab in Crohn’s FistulasInfliximab in Crohn’s Fistulas Present, D.H. et. al. N Engl J Med. 1999; 340(18):1398-405
    70. 70. Relative Contraindications toRelative Contraindications to Infliximab?Infliximab?  Open label study of 12 patients treated withOpen label study of 12 patients treated with infliximab for various forms of uveitis: observedinfliximab for various forms of uveitis: observed both PE and coronary artery thrombosis.both PE and coronary artery thrombosis.  Recommend caution in using a TNF inhibitor inRecommend caution in using a TNF inhibitor in a patient with CNS disease or a thrombotica patient with CNS disease or a thrombotic diathesis.diathesis. Rosenbaum, J.T. et. al. J Rheumatol. 2004 Jul;31(7):1241-3.
    71. 71. Our CaseOur Case  Two days into IV steroid pulse, all oral ulcers goneTwo days into IV steroid pulse, all oral ulcers gone  After IV solumedrol, started on prednisone 50mg dailyAfter IV solumedrol, started on prednisone 50mg daily  Patient discharged on 10/30/06 on prednisone 40mg dailyPatient discharged on 10/30/06 on prednisone 40mg daily  Follow-up rheumatology visit 11/9/06Follow-up rheumatology visit 11/9/06  No new oral soresNo new oral sores  Eating much better and gaining weightEating much better and gaining weight  Blurry vision improvingBlurry vision improving  Started on Cipro 11/8 for yellowish drainage from vulvar ulcersStarted on Cipro 11/8 for yellowish drainage from vulvar ulcers  Vulvar ulcer improvedVulvar ulcer improved
    72. 72. Future PlansFuture Plans  Advised smoking cessationAdvised smoking cessation  Tapered prednisone to 30mg dailyTapered prednisone to 30mg daily  TPMT*1/TPMT*3C (reference TPMT*1/TPMT*1): associatedTPMT*1/TPMT*3C (reference TPMT*1/TPMT*1): associated with intermediate enzyme activitywith intermediate enzyme activity  PPD negative in hospitalPPD negative in hospital  Plan for infliximab 5 mg/kg infusion at 0, 2, and 6 weeksPlan for infliximab 5 mg/kg infusion at 0, 2, and 6 weeks
    73. 73. ReferencesReferences  Sakane, T., et. al. N Engl J Med. 1999 Oct 21;341(17):1284-91.Sakane, T., et. al. N Engl J Med. 1999 Oct 21;341(17):1284-91.  International Study Group for Behçet's Disease. Lancet. 1990 May 5;335(8697):1078-80.International Study Group for Behçet's Disease. Lancet. 1990 May 5;335(8697):1078-80.  Tunc, R., et al. Clin Exp Rheumatol 19; 2001 S45-7.Tunc, R., et al. Clin Exp Rheumatol 19; 2001 S45-7.  www.rheumtext.com – Hochberg et al (eds)www.rheumtext.com – Hochberg et al (eds)  Letsinger, J.A., et. al. J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):500-8.Letsinger, J.A., et. al. J Am Acad Dermatol. 2005 Mar;52(3 Pt 1):500-8.  Ghate, J.V., et. al. J Am Acad Dermatol. 1999 Jan; 40 (1): 1-18.Ghate, J.V., et. al. J Am Acad Dermatol. 1999 Jan; 40 (1): 1-18.  Bhaduri, S., et. al. Int J STD AIDS. 2005 Jul;16(7):512-4.Bhaduri, S., et. al. Int J STD AIDS. 2005 Jul;16(7):512-4.  Feller, E.R., et. al. Am Fam Physician. 2001 Nov;64(10):1725-8.Feller, E.R., et. al. Am Fam Physician. 2001 Nov;64(10):1725-8.  Mat, C., et. al. Rheumatology (Oxford). 2006 Mar;45(3):348-52.Mat, C., et. al. Rheumatology (Oxford). 2006 Mar;45(3):348-52.  Barnes, C.G. Rheumatology (Oxford). 2006 Mar;45(3):245-7.Barnes, C.G. Rheumatology (Oxford). 2006 Mar;45(3):245-7.  Yurdakul, S., et. al. Arthritis Rheum. 2001 Nov;44(11):2686-92.Yurdakul, S., et. al. Arthritis Rheum. 2001 Nov;44(11):2686-92.  De Merieux, P., et. al. Arthritis Rheum. 1981 Jan;24(1):64-70.De Merieux, P., et. al. Arthritis Rheum. 1981 Jan;24(1):64-70.  Jorizzo, J.L., et. al. J Am Acad Dermatol. 1991; 24:973-8.Jorizzo, J.L., et. al. J Am Acad Dermatol. 1991; 24:973-8.  Hamuryudan, V., et. al. Ann Intern Med 1998;128:443-450.Hamuryudan, V., et. al. Ann Intern Med 1998;128:443-450.  Yazici, H., et al. N Engl J Med. 1990 Feb 1;322(5):281-5.Yazici, H., et al. N Engl J Med. 1990 Feb 1;322(5):281-5.  Masuda, K., et. al. Lancet. 1989 May 20;1(8647):1093-6.Masuda, K., et. al. Lancet. 1989 May 20;1(8647):1093-6.  Avci, O., et. al. J Am Acad Dermatol 1997;36:796–7.Avci, O., et. al. J Am Acad Dermatol 1997;36:796–7.  Alpsoy, E., et. al. Arch Dermatol 2002;138:467–71.Alpsoy, E., et. al. Arch Dermatol 2002;138:467–71.  Melikoglu, M., et. al. J Rheumatol. 2005 Jan;32(1):98-105.Melikoglu, M., et. al. J Rheumatol. 2005 Jan;32(1):98-105.  Estrach, C., et. al. Rheumatology (Oxford). 2002 Oct;41(10):1213-4.Estrach, C., et. al. Rheumatology (Oxford). 2002 Oct;41(10):1213-4.  Robertson, L.P., et. al. Rheumatology (Oxford). 2001 Apr;40(4):473-4.Robertson, L.P., et. al. Rheumatology (Oxford). 2001 Apr;40(4):473-4.  Goossens, P.H., et. al. Ann Rheum Dis. 2001 Jun;60(6):637.Goossens, P.H., et. al. Ann Rheum Dis. 2001 Jun;60(6):637.  Connolly, M., et. al. Br J Dermatol. 2005 Nov;153(5):1073-5.Connolly, M., et. al. Br J Dermatol. 2005 Nov;153(5):1073-5.  Present, D.H., et. al. N Engl J Med. 1999; 340(18):1398-405.Present, D.H., et. al. N Engl J Med. 1999; 340(18):1398-405.  Rosenbaum, J.T., et. al. J Rheumatol. 2004 Jul;31(7):1241-3.Rosenbaum, J.T., et. al. J Rheumatol. 2004 Jul;31(7):1241-3.

    ×