Rheumatology Rounds Online
Rounds XX: Evaluation and Management of Mucocutaneous Ulceration
by Ami A. Shah, MD
Release Dat...
She saw Infectious Disease in April 2005, at which time she had two persistent vaginal ulcers.
She was started on rifampin...
Physical ExaminationPhysical Examination
www.rheumtext.com - Hochberg et al (eds)
This slide is of my patient, showing her...
She was sent to the Wilmar ER, as I mentioned, on October 22. There was initial concern by the
resident for bilateral inte...
These criteria were derived by consensus from 914 patients with Behçet's disease from 12
centers in seven countries, and v...
recurrent aphthous stomatitis or non-aphthous oral disease and were excluded from the study.
That left 54 patients, or 67%...
One may ask why we bothered pursuing an EGD and colonoscopy in our patient when she had
such impressive oral and genital a...
Erythema Nodosum andErythema Nodosum and
 Clinical characteristics at baseline similar in ...
The patients were treated with varying doses of levamisole. Out of the 11 patients who had
active buccal ulcerations, nine...
Six patients in the placebo group had to be withdrawn from the study because they developed
severe eye disease. Azathiopri...
40% of the cyclosporine treated patients as compared to 15% of those treated with colchicine.
Hirsutism and renal dysfunct...
pathogenesis of pathergy, and that skin hyper-reactivity in Behçet's disease can be induced by
intradermal injection of mo...
was re-diagnosed as having Behçet's disease and was treated with infliximab 10mg/kg at week
zero and four. By the time of ...
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  1. 1. Rheumatology Rounds Online Rounds XX: Evaluation and Management of Mucocutaneous Ulceration by Ami A. Shah, MD Release Date: XX Expiration Date: XX Dr. XX has no significant financial interest or relationships to disclose. For CME credit, TAKE POST-TEST & EVALUATION This is a case of a 34-year-old African American woman with a longstanding history of furunculosis. I will be discussing evaluation and management of mucocutaneous ulcerations. The objectives of today’s rheumatology rounds are as follows: • to discuss the differential diagnosis and recommended evaluation of mucocutaneous ulceration • to discuss the current treatment options for severe disease • to recognize the current limitations of available data, namely small sample sizes, and the lack of randomized controlled trials. I met the patient in October 2006 on a Hopkins consult service. In January 2004, she had had worsening furuncles for one month, which grew MRSA. She was treated with multiple courses of antibiotics. She developed two new painful oral ulcers. In June 2004 she was hospitalized at Bayview for four days for severe pain due to furuncles and multiple vulvar ulcers that were draining purulent material. A wound culture showed MRSA and she was started on antibiotics. She had a negative HIV antibody, RPR, gonorrhea and Chlamydia probe, and HSV culture. She was discharged on Bactrim. In August 2004 she was seen by dermatology. They noticed oral and labial ulcers and prescribed Cleocin. Another HSV culture was negative. She was restarted on Bactrim. In September, the same findings were visualized. At this time, they considered Crohn’s, Reiter’s and Behçet's disease, but referred the patient to Infectious Diseases. She had an HSV culture sent again that was negative. She was prescribed Zovirax cream and Bactrim. In October 2004, there was a three-week period when she had no oral or genital ulcers whatsoever while on Bactrim. She discontinued her therapy. In November she had a recurrence of her sores, requiring re-institution of the medication. In December she sought Infectious Diseases service. She had vulvar ulcers, furuncles, and labial ulcers in her mouth. She had a negative viral culture for HSV. Again, pemphigus and Behçet's disease were considered. The patient was anemic at that time, but had a normal sedimentation rate. Infectious Disease recommended that dermatology biopsy one of these lesions. In March, when she saw dermatology, she was on Bactrim twice a day since October or November; however, she had continuous outbreaks of her ulcers, with all of her lesions lasting longer. She had very impressive vulvar and oral ulcers, and multiple comedones were noted. She had acne scarring. In her right cheek she had an erythematous nodule about 1cm. Biopsy and Accutane were considered. Herpes antibodies were resent.
  2. 2. She saw Infectious Disease in April 2005, at which time she had two persistent vaginal ulcers. She was started on rifampin and minocycline for recurrent skin abscesses due to her MRSA. She had many courses of Valtrex without improvement. Up to this point she had been seen by dermatology and infectious diseases services and had gotten quite frustrated that she had no diagnosis and was not responding to antibiotic or antiviral therapy; she gave up on all of these physicians there. She then used the ER for the rest of 2005 and 2006 due to severe pain from her vulvar ulcers. She would get loaded up on IV Dilaudid; she was discharged every time. In October 2006, she presented to an urgent care center with genital ulcers that were infected with E. coli and Klebsiella. She had a CT scan that showed some soft tissue thickening of the labia majora and minimal stranding around her perirectal region. She was called when this culture came back positive. She went to the ER in October 20 with significant genital pain, fever, and inability to eat due to oral sores. She had lost 30 lbs since 2003. She also complained of blurry vision for the past month. Given this prior culture, she was admitted to the gynecology service and treated with Zosyn and fluconazole. As she mentioned to the gynecology resident, she awoke with a big, black spot in the center of her vision, blurry peripheral vision, and white flutters in her left eye. They sent her over to the Wilmar ER. Past medical history Her past medical history is notable for polycystic ovarian syndrome, status post-laparoscopy and ovarian cystectomy. She also had a history of drug abuse, asthma, anemia, and migraines. She was on pHisoHex, which has chlorhexidine and lidocaine, which she was applying to her ulcers topically, as well as Imitrex as needed. She had no drug allergies. There was no family history of autoimmune disease, and she was actively smoking six to seven cigarettes a day. She denied any IV drug use, but last smoked cocaine and marihuana two weeks prior. When I met her, her T max was 39.2, her weight was 35 kg, and she was cachectic in appearance. She had numerous open comedones and pitted scars on her face. On the left lateral aspect of her tongue there was a 1cm oval lesion with a pseudomembrane overlying it, and a slightly hyperemic border. She had a similar lesion on the left side of her tongue, and two healing ulcers on her lower lip. She did have a systolic murmur. Pulmonary and abdominal examinations were unremarkable. She had faint hyperpigmented papules on her bilateral chin. There was no pathergy at her blood draw sites. Her neck was supple. She had no photophobia, and she had a normal cranial nerve and strength exam. She had no synovitis. This is not my patient, unfortunately. We were not able to get a photo of her ulcers, but this is what they looked like, but in a different patient. This is from the Hochberg text.
  3. 3. Physical ExaminationPhysical Examination www.rheumtext.com - Hochberg et al (eds) This slide is of my patient, showing her genital ulceration and the loss of her labia majora, which have been completely eroded. This had been brewing for three years, treated with antibiotics and antiviral therapy.
  4. 4. She was sent to the Wilmar ER, as I mentioned, on October 22. There was initial concern by the resident for bilateral intermediate uveitis with possible macular infarction and macular edema in the right eye, as well as some vitreous hemorrhage in the left eye. She was started on solumedrol 1gm IVq24h x 3 doses based on these findings. After the first dose, she was seen by the ophthalmology attending the next day, who commented on only mild non-specific findings of ocular inflammation. They did a fluorescent angiogram, which was not suggestive of retinal vasculitis. She went to the OR for wound debridement the next day, and for right vulvar and perianal biopsy, which was recommended by dermatology and infectious diseases. Her cytopathology showed squamous metaplasia, which, according to gynecology, is a normal finding in a woman of her age. She had a right labial and perianal skin biopsy which showed diffused lymphohistiocytic inflammation ulcer that could be consistent with Behçet's disease. She denied any hematochezia or diarrhea, but had an EGD and colonoscopy done, which showed mild gastritis only. Infectious Diseases was concerned about histoplasmosis, LGB, HIV, and malignancy. Their workup was unremarkable. Given her history of migraines and concern for neural Behçet's disease, we obtained an MRI of the brain, which was unremarkable. We saw her the day after she had been seen by the resident at the ER. The data that we had was a resident’s interpretation of ocular inflammation. It was before we had any pathology. This pathology actually did not come back until well after her discharge. At that time, we were concerned about Behçet's disease, but we were also considering inflammatory bowel disease as well as many other things in our differential diagnosis. We agreed with steroid therapy at that time, and did not feel strongly that a biopsy needed to be done because we were not sure that it would be particularly helpful. We had a fairly high clinical suspicion of what was going on. Evaluation of mucocutaneous ulceration Behçet's disease is a multi-system inflammatory disorder that was first described in 1937 as a triad of oral ulcers, genital ulcers, and uveitis. There is an increased prevalence along the ancient Silk Road in Asia and the Middle East. In Turkey, the prevalence is 80 to 370 per 100,000 as compared to the United States where it is less than one per 100,000. There is an association with HLA-B51 in all ethnic groups, but it is less predictive of disease in Western populations. The International Study Group (ISG) for criteria Behçet's disease were developed in 1990. (Prior to this, there were four or five different criteria for establishing the diagnosis of Behçet's disease, which made it very difficult to follow clinical trials.) In the absence of other clinical explanations, patients should have recurrent oral ulcers defined as minor aphthous, major aphthous, or herpetiform ulcers as observed by a physician or a patient at least three times in a 12 month period. In addition, they should have recurrent genital ulceration, eye lesions, skin lesions, and positive skin pathergy test. The eye lesions include anterior and posterior uveitis, or cells in the vitreous on slit-lamp exam, or retinal vasculitis. The skin lesions can include erythema nodosum, pseudofoliculitis, or papulopustular lesions. Also acneic foreign nodules, as long as they are in a post-adolescent patient who is not receiving corticosteroids, are considered to be one of the criteria.
  5. 5. These criteria were derived by consensus from 914 patients with Behçet's disease from 12 centers in seven countries, and validated in a large cohort of 300 patients with Behçet's disease. In 440 patients with other diagnoses, including IBD, it was found to have 98% sensitivity and 99% specificity for Behçet's disease. Frequency of the ClinicalFrequency of the Clinical Manifestations of BehManifestations of Behççetet’’s Syndromes Syndrome and the ISG Diagnostic Criteriaand the ISG Diagnostic Criteria www.rheumtext.com – Hochberg et al (eds) The above is slide reviews the frequency of some of the clinical manifestations of Behçet's disease. • Oral ulcers are seen universally in all the patients as it is part of the diagnostic criteria. • Genital ulcers are seen in approximately 85% of patients. • Papulopustular lesions are seen in 85% of patients. • Erythema nodosum is seen in 50%. • Additionally, uveitis, arthritis, thrombophlebitis, DVT, arterial occlusion, aneurysm, CNS involvement, epididymitis, and gastrointestinal lesions can be seen. In order to make a diagnosis of complex aphthosis you must have constant presence of multiple oral ulcers, or recurrent oral and genital ulcers, and the exclusion of Behçet's disease. This can be primary—which is idiopathic—or secondary. The major secondary causes of complex aphthosis are IBD, HIV, celiac disease, cyclic neutropenia, agranulocytosis, vitamin deficiencies, and FAPA (fever, aphthous stomatitis, pharyngitis, adenitis syndrome). There have also been some possible implications of food allergies to cow’s milk, gluten, food dyes, and preservatives. A group at Wake Forest, from 1995 to 2001, looked at 81 patients who were referred for evaluation of possible Behçet's disease. (Applying the ISG criteria to these patients, 10 were diagnosed with Behçet's disease.) Many did not have complex aphthosis. Seventeen had simple
  6. 6. recurrent aphthous stomatitis or non-aphthous oral disease and were excluded from the study. That left 54 patients, or 67% of the initial population, with complex aphthosis. Out of those, 12 had complex aphthosis due to another cause. Ten of the 12 had IBD, one had HIV, and one had cyclic neutropenia. Out of the 42 who were deemed to have idiopathic complex aphthosis, 13 had confirmed genital ulcers. In over six years of follow up, none of the patients with idiopathic aphthosis went on to develop Behçet's disease. However, the authors cautioned that since oral ulcers can manifest six to eight years before any other manifestations, the patients need to be followed closely. Thirty-nine out of the 42 were treated with topical steroids. All received systemic therapy with colchicine, dapsone, or thalidomide. They used the following algorithm to arrive at a diagnosis: The Wake Forest ExperienceThe Wake Forest Experience 19951995--20012001 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%) • If somebody had oral aphthae, they were asked, “Do you have less than three?” If so, they have recurrent aphthous stomatitis. • If there were more than three, almost constant oral aphthae, or oral and genital aphthae, the patient were evaluated by the ISG criteria. • Likewise, if the patient had general aphthae, he or she was first evaluated for herpes. If that was negative, the ISG criteria were applied. • Those who did not meet diagnostic criteria for Behçet's disease were labeled as having complex aphthosis. They were worked up with the appropriate laboratory tests and gastrointestinal evaluation. HIV, HLA-B27, and anti-gliadin antibody testing were also considered. Some other things they considered in the differential diagnosis of Behçet's disease included reactive arthritis, IBD, multiple sclerosis, sarcoidosis, other vasculitides, and viral infections.
  7. 7. One may ask why we bothered pursuing an EGD and colonoscopy in our patient when she had such impressive oral and genital aphthae. This is because there are case reports of Crohn’s disease of the vulva. In one report, the gastrointestinal symptoms developed three years after biopsy-proven Crohn’s of the vulva. Gynecologic complications in Crohn’s include fistulas from anywhere in the bowel to GYN structures to granulomatous salpingitis and oophoritis as well as vulvar inflammation and ulceration. Systemic medical management of mucocutaneous ulcers in Behçet's Corticosteroid therapy A study of corticosteroid therapy published in 2006 included 86 patients with active Behçet's disease and at least one genital ulcer in the preceding six months. The researchers excluded patients who had had immunosuppressive agents or corticosteroids at 5mg per day in the preceding month, severe organ involvement including ocular inflammation, diabetes, active infection, peptic ulcer disease, hypertension, or pregnancy. Patients were allowed to continue previous therapy with colchicine, low-dose aspirin, amitriptyline, acetaminophen, or NSAIDS. They were allowed topical treatment and systemic thalidomide if they had severe oral and genital ulceration. The patients were randomized to 40mg methylprednisolone IM or placebo saline injections every three weeks for 27 weeks. This dose was picked because of a concern about side effects from steroids at a higher dose. The primary outcome measure was the difference in mean numbers of genital ulcers between the two groups. Secondary outcomes were the difference in the mean numbers of other mucocutaneous lesions and attacks of arthritis. Eighty-eight percent of study patients completed the treatment. One male from each group was withdrawn from the trial because of development of eye disease; one female from each treatment required thalidomide therapy, one for severe genital ulcers and one for severe oral ulcers. There was no significant difference in the mean number of genital and oral ulcers or folliculitis between the groups. Because the mean half-life of IM methylprednisolone is 139 hours, the researchers postulated that perhaps there was no difference because they under-dosed their patients or gave it too infrequently. They also said that since skin infection may play some role in the pathogenesis of the manifestations of Behçet's disease, that may explain why they patients not respond to steroids. They evaluated their patients separately based on gender, as males tend to have more severe disease. The clinical characteristics at baseline were similar in the treatment and placebo groups except that the steroid group had significantly fewer patients with a history of erythema nodosum. As you can see in the highlighted part of the table, there is initially a statistically significant difference for women only with respect to erythema nodosum between the steroid and no treatment arms. However, that statistical significance disappeared in the post-treatment period. The authors postulated that the disappearance of that significance difference between the treatment and placebo groups with cessation of therapy could suggest that corticosteroids have an effect on erythema nodosum among women.
  8. 8. 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. Colchicine A study published in 2001 in Arthritis & Rheumatism (Yurdakul, S., et. al. Arthritis Rheum. 2001 Nov;44(11):2686-92) looked at colchicine treatment in 116 patients with Behçet's disease —60 men and 56 women with active mucocutaneous disease defined by at least three episodes in the last six months. Patients with eye or major organ involvement were excluded as were those who had been on colchicine, steroids, or any other immunosuppressant therapy in the preceding six months. The 116 patients were randomized to placebo or colchicine 1-2 mg per day adjusted to body weight. The trial was double-blind trial and for two years. The researchers defined a complete response as the sustained absence of any lesions including ulcers, erythema nodosum, and follicular lesions as well as a sustained absence of arthritis during therapy. Their secondary outcome measure was the difference in the number of mucocutaneous lesions and arthritic joints between the active drug and placebo groups. Women and men were analyzed separately. Seventy-two percent completed the 24 month trial. Results show that efficacy was not the same for colchicine in men and women. It was clearly effective for arthritis in both groups, but the beneficial effects of colchicine on erythema nodosum and general lesions were only seen in women. Levamisol Levamisole has also been studied in Behçet's patients (De Merieux, P., et. al. Arthritis Rheum. 1981 Jan;24(1):64-70). It has been used to treat recurrent aphthous stomatitis. It is an anti- helminthic drug that has been used in colon cancer as adjunctive therapy and in the treatment of lice. This study of levamisole was an open trial of 11 patients, two who had complete Behçet's by Japanese criteria, 8 with incomplete, and 1 with suspected. This was done in 1981 before the ISG criteria were formulated.
  9. 9. The patients were treated with varying doses of levamisole. Out of the 11 patients who had active buccal ulcerations, nine improved with therapy. Four of the nine had a complete response and five had a partial response. When treatment was interrupted in three patients, all flared. Two improved with re-initiation of therapy. Methotrexate Methotrexate is less well studied. There is a report of two patients with Behçet's disease and active mucocutaneous disease, which in these patients consisted of cutaneous pustular vasculitis, pyoderma-like lesions, and oral and genital aphthae (Jorizzo, J.L., et. al. J Am Acad Dermatol. 1991; 24:973-8). Treatment with multiple other agents had failed including NSAIDS, colchicine, intralesional steroids, dapsone, azathiaprine, and chlorambucil. With methotrexate, the same patients had resolution of their disease at three weeks and two months, at doses of 15 and 20mg, respectively. The patients who had been steroid-dependent were able to taper off their steroids. Thalidomide Thalidomide is better studied. Most trials are from a center in Istanbul, Turkey including a randomized, double-blind, placebo-controlled trial looking at Behçet's patients from 1993 to 1996. The study enrolled 96 male patients with active mucocutaneous lesions but no major organ involvement, no recent immunosuppressant therapy, and no clinical neuropathy. The patients were randomized to thalidomide 100mg once a day, 300mg once a day, or placebo for 24 weeks. They were followed for four weeks after treatment ended. Males were deliberately selected because of the severity of the disease as well as the teratogenicity of thalidomide. The researchers collected data about the number of new lesions. A complete response was defined as the sustained absence of any oral or genital ulceration during treatment. They also measured the changes and the number of mucocutaneous lesions. Polyneuropathy developed in one patient in the 100mg group and in three in the 300mg group. Three were diagnosed with polyneuropathy after the trial ended. In the 100mg group, six percent of patients had a complete response; in the 300mg group, 16%; and none of the placebo patients. Most of the treatment failures occurred in the first four weeks. If patients were going to respond, they typically did so within the first four weeks of therapy. For genital ulcers and follicular lesions, they typically responded within the first eight weeks. Interestingly, both doses increased the numbers of erythema nodosum lesions. This actually resolved itself typically by the eighth to 12th week time point. This was dose-independent effect that persisted during therapy but diminished rapidly after thalidomide was discontinued. Azathioprine Azathioprine has also been studied, primarily looking at ocular inflammation. Researchers compared a group without eye disease and a group with eye disease in a two-year randomized, placebo-controlled, double-blind trial of azathioprine 2.5mg/kg once a day in men with Behçet's disease (Yazici, H., et al. N Engl J Med. 1990 Feb 1;322(5):281-5). They were looking to see whether azathioprine would prevent development of eye disease or prevent worsening of existing eye disease. They excluded patients who already had irreversible bilateral eye disease who had had immunosuppressive therapy in the last three months or steroids in the last month. Steroid therapy was available to all.
  10. 10. Six patients in the placebo group had to be withdrawn from the study because they developed severe eye disease. Azathioprine was found to be superior to placebo in the prevention of new eye disease in group one and in group two among the 14 patients who had disease in only one eye at entry. There were few episodes of hypopyon uveitis among the group two patients on azathioprine. The researchers also looked at extraocular manifestations in response to azathioprine. Azathioprine did not prevent the development of new oral ulcers, but it did improve healing. Among those who initially did not have genital ulcers, three on azathioprine group developed them as compared to 12 of placebo. That was statistically significant. There was no effect on papulopustular lesions with azathiaprine. Extraocular ManifestationsExtraocular Manifestations number of patients (percent) Present at 24Present at 24 MonthsMonths New DuringNew During TrialTrial Present atPresent at Initial VisitInitial Visit Ever PresentEver PresentManifestationManifestation 17 (74)17 (74)27 (79)27 (79)11 (85)11 (85)1111 (79)(79) 23 (64)23 (64)23 (62)23 (62)29 (81)29 (81)28 (76)28 (76)PapulopustularPapulopustular lesionslesions 0 (0)0 (0)0 (0)0 (0)7 (21)7 (21)6 (19)6 (19)3 (8)3 (8)5 (14)5 (14)11 (31)11 (31)20 (54)20 (54)ErythemaErythema nodosumnodosum 8 (13)8 (13)1 (3)1 (3)12 (38)12 (38)3 (10)3 (10)4 (11)4 (11)6 (16)6 (16)29 (80)29 (80)32 (86)32 (86)GenitalGenital ulcerationulceration 8 (35)8 (35)4 (12)4 (12)7 (47)7 (47)1111 (52)(52) 21 (58)21 (58)16 (43)16 (43)36 (100)36 (100)3737 (100)(100) Oral ulcerationOral ulceration PlaceboPlacebo (N = 23)(N = 23) AZAAZA (N = 34)(N = 34) PlaceboPlaceboAZAAZAPlaceboPlacebo (N = 36)(N = 36) AZAAZA (N = 37)(N = 37) PlaceboPlacebo (N = 36)(N = 36) AZAAZA (N = 37)(N = 37) 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 imprAZA may not prevent development of new oral ulcers but may improve healingove healing •• Among those initially without GU, 3 in AZA vs 12 in placebo devAmong those initially without GU, 3 in AZA vs 12 in placebo developed GUeloped GU •• No effect on papulopustular lesionsNo effect on papulopustular lesions Cyclosporine Cyclosporine has also been studied. An example is a study of 96 patients applying the Japanese 1982 criteria (Masuda, K., et. al. Lancet. 1989 May 20;1(8647):1093-6). The patients had a visual acuity of less than 20/40 and at least two ocular attacks during the 16 weeks before the study began. They were randomized to cyclosporine 10mg/kg once a day or colchicine 1mg once a day for 16 weeks. The dose was reduced or discontinued treatment if in patients who developed significant side effects. The researchers graded oral aphthous ulcers, dermal lesions, and genital ulcers into four grades based on the frequency and number of lesions. Cyclosporine alleviated oral aphthous ulcer in 70% as compared to only 20% in the colchicine group. Dermal lesions were also alleviated in
  11. 11. 40% of the cyclosporine treated patients as compared to 15% of those treated with colchicine. Hirsutism and renal dysfunction was quite common in the cyclosporine group. Another study looked at cyclosporine in 30 patients with Behçet's disease who had pathergy and active mucocutaneous disease (Avci, O. et. al. J Am Acad Dermatol 1997;36:796–7). The patients were treated with a lower dose of cyclosporine, 5mg/kg once a day; the dose was adjusted based on renal function. Six patients were excluded due to irregular drug use;19 men and 5 women were treated for more than six months. Out of these 24 patients all had oral ulcers pre-treatment. Treatment resulted in significantly longer symptom-free intervals and decrease in the average number and size of oral ulcers. Twenty-five percent had no oral ulcers during therapy. Out of tose who were followed consistently, 21 had genital ulcers pre-treatment, and 80% had no general lesions during therapy. Two patients worsened. Interferon α-2a Interferon α-2a has also been studied. One study enrolled 50 patients with Behçet's disease defined by the ISG criteria (Alpsoy, E., et. al. Arch Dermatol 2002;138:467–71). Patients with major organ involvement, coagulopathy, recent systemic or topical therapy, as well as retinal vasculitis or cerebral disease were excluded. The researchers first observed the study patients for three months, recordingall the attacks. They then randomized the patients interferon α-2a or placebo three times a week; the patients were followed weekly up until three months post- treatment. A complete response was defined as the disappearance of all signs and symptoms. In the interferon group, two out of three met this criterion. A partial response was defined as a more than 50% decrease in the frequency, duration, and severity of pain for oral and genital ulcers, or a decrease in the severity and frequency of attacks for ocular involvement. Thirteen out of 23 in the interferon group and 3 out of 21 in the placebo group met this response. Stable disease was defined as less than 50% change in signs and symptoms; four of 23 in the interferon group and three of 21 in the placebo group fell into this category. In terms of frank worsening, 15 of the 21 in the placebo group worsened as compared to four of 23 in the interferon group. Six patients were unable to complete the study. This was due to severe eye disease in three (one in the interferon group, progressive mucocutaneous symptoms in one(in the interferon group), new eye disease and mucocutaneous symptoms (one in the placebo group), or progressive mucocutaneous and articular symptoms (one in the placebo group). Interferon decreased the duration and pain of oral ulcers and it did so rapidly. This was statistically significant. It also decreased the frequency of general ulcers and papulopostular lesions. The frequency and duration of erythema nodosum and thrombophlebitis was also improved, but not statistically significantly. All symptoms returned to pre-treatment levels very rapidly once therapy was discontinued. Etanercept In this 2005 study of etancerpt (Melikoglu, M., et. al. J Rheumatol. 2005 Jan;32(1):98-105) The researchers looked its effect on pathergy, and monosodium murate (MSU) test reactions. They postulated that the presence of T cell monocyte and macrophage infiltration and the expression of interferon gamma and IL-12 suggested TH1 type of immune response in the
  12. 12. pathogenesis of pathergy, and that skin hyper-reactivity in Behçet's disease can be induced by intradermal injection of monosodium murate crystals. They defined a positive MSU test as a persistent area of erythema at the injection site at 48 hours, and stated that the sensitivity of this for Behçet's disease was 61% to 78% and the specificity was 94% to 100%. The study to evaluate the effect of etanercept on these reactions was a double-blind and placebo- controlled trial. It included men with clearly positive pathergy and monosodium murate test at enrollment. In the preceding three months, subjects must have had an oral ulcers, genital ulcers, modular lesion, or swollen joints. Again, excluded were patients with serious organ involvement, history of TB or recent infection, use of etanercept in the last four weeks, transaminitis anemia, leucopenia, thrombocytopenia, or renal dysfunction. Forty patients were randomized to etanercept twice weekly or placebo for four weeks. Eighteen patients on colchicine and five patients on azathioprine underwent a drug four-week washout period prior to beginning the study. The pathergy and MSU tests were performed at the initial visit, weeks 1 and weeks 4, and three months after the trial ended. There was a statistically significant improvement in oral ulcers and nodular lesions by week 1; however, this was not sustained at three months. There was no improvement in genital ulcers, pathergy, or the monosodium murate tests. The researchers postulated that the lack of effect on general ulcers could be due to the small sample size and relative infrequence of genital ulceration in their population. Infliximab In a case where a patient failed to respond to etanercept, infliximab elicited a better response. This is a case of a 38-year-old woman with Behçet's disease who had severe oral and genital ulcerations as well as iritis. She had no benefit from topical triamcinolone, colchicine, cyclosporine, pulsed high-dose IV steroids, chlorambucil, or thalidomide. They tried etanercept 25mg twice weekly for three months; she had no improvement. The patient was then switched to infliximab 3 mg/kg at weeks zero and two, and then every eight weeks thereafter. She was also on methotrexate 7.5mg every week. After the first infusion, she had resolution of her oral and genital ulcerations and erythema nodosum. One year later, on continued therapy on infliximab, she was in remission. In another patient who had Behçet's disease by ISG criteria, persistent ulceration for 10 years, and failure to respond to thalidomide, dapsone, azathiaprine, colchicine, and cyclosporine, a trial of infliximab 5 mg/kg at week zero, two, and six resulted in a marked decreased in the number of her ulcers. The effect was observed after the first infusion. She had no ulcers after the third infusion and a sustained response. A third case is that of a 40-year-old man who was initially diagnosed with PAN in 1986 due to painful nodules and foot ulcers as well as pathology. He had persistent disease activity on prednisone, azathioprine, and cyclophosphamide. He was steroid-dependent and had no remission when he received IV cyclophosphamide therapy or thalidomide. In September 1999, 13 years after his initial presentation, he developed oral, anal, and penile ulcers, and was treated with prednisone and methotrexate. At this point, an ophthalmologist noted retinal vasculitis. He
  13. 13. was re-diagnosed as having Behçet's disease and was treated with infliximab 10mg/kg at week zero and four. By the time of his second infusion he had no ulcers. He remained in remission at least 12 months after his last infusion. Again, he only received two doses. A fourth case demonstrating use of infliximab is of a 39-year-old woman with Behçet's disease who had worsening oral and genital ulcerations, severe arthralgias, and uveitis. Between the ages of 25 and 39 she failed multiple agents. She was doing okay on thalidomide but then developed significant peripheral neuropathy; when thalidomide treatment was discontinued she experienced severe rebound of her oral, pharyngeal, and genital ulcerations. She was tried on infliximab 3mg/kg and methotrexate. Within two days all her ulcerations began to heal. She had no relapse after 12 months of therapy. You may be wondering why, out of all of these agents, I am advocating for treatment with infliximab. The answer is based on the literature on a randomized, multicenter, double-blind, placebo-controlled trial of infliximab for fistulas in 94 adults with abdominal and perianal fistulas for at least three months due to Crohn’s disease (Present, D.H. et. al. N Engl J Med. 1999; 340(18):1398-405). The patients were randomized to receive placebo, 5mg/kg of infliximab, or 10mg/kg of infliximab at weeks zero, two, and six. The primary end point was a more than 50% reduction in the number of draining fistulas, observed on two or more consecutive visits. Sixty-eight percent in the low-dose group, 56% in the higher-dose group, and 26% in the placebo group met this end point. The findings were statistically significant. The secondary end point was closure of all fistulas. Again, the 5mg/kg group did the best. The median length of time during which the fistulas remained closed was three months. Infliximab, however, is not a benign drug. In an open-label study of 12 patients treated with infliximab for various forms of uveitis the researcher observed PE and coronary artery thrombosis in two of the 12 patients; caution was recommended when using TNF inhibitors in patients with Behçet's disease, as they are prone to CNS disease and thrombotic complications. Retunring to today’s patient, two days into her IV steroid pulse, her oral ulcers completely resolved. That is the reason I do not have a photo to show; the ulcers where gone by the time I returned with a camera. After IV solumedrol, she was started on prednisone 1mg/kg daily, and at discharge she was sent home on 40mg prednisone a day. I saw her back in clinic on November 9 at which time she had no new oral sores. She was eating better and gaining weight. Her blurry vision was continuing to improve. She had been started on Cipro by gynecology the day before for yellowish drainage which she had described over the phone. Her vulvar ulcer had improved. The response was quite impressive. The patient was asked to stop smoking. Her prednisone was tapered to 30mg once a day. Her TPMT study was associated with intermediate enzyme activity. Her PPD was negative. The plan is to start her on infliximab in the next week, at 5mg/kg at weeks zero, two, and six. ###