Malattia di Behet

 

BENEFICIAL EFFECTS OF INTERFERON ALPHA TREATMENT IN REFRACTORY BEHCET DISEASE.

Meral Calguneri, Mehmet AKIF Ozturk, Sedat Kiraz, Ihsan Ertenli, Sule Apras, Zeynep Ozbalkan Ankara, Turkey

Behcet disease (BD) is a chronic multisystem disorder of unknown etiology in which orogenital ulcerations, uveitis, skin lesions, thrombosis of veins and arteries, vascular aneurisms and neurologic signs are prominent features. There is still no effective regimen for BD and significant morbidity have been reported in patients with ocular involvement. Previous studies revealed promising results with interferon (IFN)alpha for ocular, mucocutaneuos and arthritic manifestations of BD. In this open trial, we administered IFN alpha2a to our group of BD patients who were resistant to conventional therapies. The study population consisted of 13 patients (male/female: 7/6, mean age: 35.9 months). All of the patients fullfilled the International Study Group Criteria for BD. Clinical features of the study group is given in table 1.IFN alpha therapy was given by self-administered dose of 5 million units subcutaneously three times a week, and the dose was tapered to 3 million units three times a week and later to 3 million units twice a week in 6 patients after CR was achieved. Median therapy duration was 18 months (range: 3-66 months). Data were extracted and evaluated according to the following criteria: complete remission (CR), disappearance of all manifestations during treatment; partial remission (PR), greater than 50% decrease in the number, severity, duration and/or frequency of recurrence of the lesions; stable disease (SD), less than 50% change in the manifestations; and progressive disease, greater than 50% deterioration of existing manifestations or/and the development of new ones. All of the patients experienced clinical improvement with this therapy (CR, PR, and SD in 8, 3, and 2 patients, respectively). Partial improvement was recorded in neurologic manifestations in two patients with neurologic involvement and one patient with Budd Chiari syndrome. Two patients with arthritis experienced recurrences within 3 months after dose reduction or discontinuation of therapy. Mild adverse effects such as fever, nausea and myalgias were generally recorded during the early phase of therapy; however no patient had to discontinue IFN alpha because of intolerance. These results indicate that subcutaneous human recombinant IFN alpha appears to be an effective and well tolerated therapy for BD.

Table 1. Clinical features of the patients

 

oral ulcer genital ulcer skin lesion pathergy uveitis neurological manifestation vascular manifestation arthritis

13/13        13/13         9/13        3/13    8/13             2/13                       3/13             6/13

 

THE CLINICAL SIGNIFICANCE OF A PATHERGY REACTION IN KOREAN PATIENTS WITH BEHCET'S DISEASE.

Hyun Kyu Chang, Kyeong Soo Cheon Kangnung-City, Kangwondo, Republic of Korea

Objective: To reevaluate the frequency of a positive pathergy reaction (PR), the intensity and disease specificity of this reaction in Behcet's disease (BD) when a disposable needle was used, to assess the clinical association between the PR and the clinical feature of BD or its disease activity, and to clarify whether the patients with a pustule formation at the venous puncture site (venous PR) without positive PR could be regarded as a positive reaction.

Methods: The study population included 64 patients with BD, 74 patients without BD, and 20 healthy controls. The PR was done by the intradermal prick with a disposable 21 gauzed needle. The results were read at 48 hours, and were graded as follows; grade 0: needle mark or erythema only, grade 1: papule, grade 2: pustule. Venous PR was done in 8 BD patients having a pustule formation at the venous puncture site, and in 10 patients without BD. In 14 patients with a positive PR, either PR or venous PR, the test was repeated during relatively quiescent phase of disease. The clinical activity score (CAS) was calculated by summing each clinical manifestation existed when a PR was performed.

Results: The PR was positive in 35.9% of BD patients, and in the only 1 patient among patients without BD. There were no persons with a positive PR in healthy controls. In addition, grade 2 reaction was only observed in 1 patient with BD. There was no statistical significance between a positive PR and the clinical variables, such as onset of age, sex, skin lesions, genital ulcers, uveitis, gastrointestinal lesion, arthritis, or HLA-B51. The mean CAS of BD patients with positive PR was 2.911.31, and that in BD patients with negative PR was 2.851.17. Venous PR was positive in 7 among 8 BD patients, in whom PR was only positive in three among these patients. However, venous PR was negative in all ten patients without BD. The PR was positive in 2 patients during inactive phase among 14 patients with positive reaction.

Conclusions: 1)The PR proved to be relatively specific, and the prevalence of positive PR was 35.9% in Korean BD patients. 2)The frequency of intense reaction was very rare. 3) A positive PR was not associated with onset of age, sex, the clinical features, and the presence of HLA-B51 in BD. 4) Although the PR was not related with the disease severity of BD, it was usually found in the active phase of the disease. 5) For patients with a pustule formation at the venous puncture site, it seems to be considered as a positive reaction, especially in patients who have the clinical features of BD

 

THE COMPARISON BETWEEN BEHCET'S DISEASE AND SPONDYLOARTHRITIDES. DOES BEHCET'S DISEASE BELONG TO A PART OF SPONDYLOARTHROPATHY COMPLEX.

Hyun Kyu Chang, Deok Hee Lee, Seung Mun Jung, Jeong Uk Kim, Eun Hee Cho Kangnung-City, Kangwondo, Republic of Korea

Objective: The inclusion of Behcet's disease (BD) into the spondyloarthropathy (SpA) complex is still some debatable. To date, the studies for this issue has been mainly limited to whether the prevalence of sacroiliitis (SI) or ankylosing spondylitis (AS) is greater in patients with BD. Therefore, this study was undertaken to clarify whether it is suitable that BD could be classified into one of SpA complex.

Methods: This study have prospectively undertaken for 58 patients with BD (BD group) who satisfied the criteria by the International Study Group, 56 patients with SpA (SpA group) who fulfilled the criteria by the European Spondyloarthropathy Study Group, and 3 patients who concurrently satisfied the criteria for BD and SpA (BDSpA group). The clinical parameters such as SI, enthesitis, the pattern of eye involvement, and known susceptible HLA antigens (HLA-B27 and B51) were compared in the BD group and SpA group. In addition, 3 patients in BDSpA group were reviewed.

Results: The SI was found in 58.9% of SpA group, in 10.3% of BD group, and in 3.6 % of healthy controls. The prevalence of definitive SI of BD group and SpA group was 46.4% and 5.2%, respectively. However, there was no person with that in healthy controls. Enthesitis was observed in 3.4% of BD group and in 50% of SpA group. The ocular involvement in BD group was found in 12 patients (20.7%) as the following patterns: 7 patients with anterior and posterior uveitis, 2 patients with posterior uveitis and retinal vasculitis, 2 patients with anterior uveitis, and 1 patient with scleritis. However, this in SpA group was occurred in 17.9% of patients in whom all ten patients had anterior uveitis. In addition, HLA-B27 was negative in all 49 patients of BD group, and this was positive in 67.9% of SpA group. The prevalence of HLA-B51 in BD group was 51.7%, and 21.4% in SpA group. Patient 1 in BDSpA group was considered as a real case concurrently having BD and AS. Patient 2 was closer to AS, and patients 3 to BD.

Conclusion: BD seems to be associated with HLA-B51 rather than HLA-B27. Patients with SI or enthesitis were found in a minor portion of BD group. In addition, the pattern of eye involvement in BD group was different to that in SpA group. Therefore, it seems that BD could not classified into SpA complex. However, it remains still unclear why there have been many patients with coexisting BD and AS or SpA, including our cases

 

ROLE OF CLASSICAL THROMBOGENIC FACTORS IN DURAL SINUS THROMBOSIS (DST) DUE TO BEHCET'S DISEASE (BD): A STUDY OF 40 PATIENTS.

Bertrand Wechsler, Du Le Thi Huong, Abdallah Sibai, Jean-Charles Piette Paris, France

Methods: since 1974 we have followed 54 patients with Behcet's disease (BD) and dural sinus thrombosis (19 women and 35 men) native from France (n=16), North Africa (n=21), Africa (n=6) and other mediterranean areas (n=11). Age ranged 9 to 36 years at time of DST (mean 29.6).

Determination of classical thrombogenic factors was performed in 40 pts including anticardiolipin antibodies in 32, antithrombin III in 33, protein S in 30, protein C in 33, G1691 --> A factor V Leiden mutation, methylene tetra hydrofolate reductase (MTHFR) C677 --> T mutation and G20210 --> A prothrombin gene mutation in 27, 20 and 18 cases respectively, and homocysteine level in 17. All these tests were realized in 13 pts.

Results: anticardiolipin antibodies were negative in all patients. Levels of antithrombin III and protein C were normal in all. One patient had protein S level reduced to 60% of normal value. Heterozygous mutation of factor V and of prothrombin gene was observed in one case each (3.7% and 5.6% respectively).

One patient (5%) was homozygous and 10 (50%) were heterozygous for the MTHFR C677 --> T mutation. Homocysteine level was elevated in only 3 patients, of which one was homozygous and another heterozygous for the MTHFR C677 --> T mutation.

Conclusion: classical thrombogenic factors are rarely encountered in patients with BD complicated by DST, with the possible exception of hyperhomocysteinemia. The mechanisms leading to venous thrombosis in BD remain to be elucidated.

 

TREATMENT OF REFRACTORY POSTERIOR UVEITIS WITH ANTI-TNF-ALPHA (INFLIXIMAB).

Antonio Banares, Lydia Abasolo, Pilar Macarron, Cesar Hernandez, Juan A Jover, Benjamin Fernandez, Esperanza Pato Madrid, Spain

Monday, November 12, 2001, 7:30 AM, Poster Session: Treatment, Epidemiology and Diagnosis of Spondyloarthropathy (7:30 - 9:00 AM) Board Number: 227 Exhibit Hall D and E, Moscone

There is a group of patients with non-infectious posterior uveitis (PU) who are refractory to corticosteroid or immunosuppressive (IS) regimens.

OBJECTIVE : To demonstrate the efficacy of infliximab in the treatment of non-infectious PU.

PROTOCOL: open and non-controlled trial including 7 patients with corticosteroid-refractory PU who were receiving one or more of the following IS agents for a minimum of 2 years: CsA, AZA, MTX. Treatment was administered on a compassionate use basis, after EC approval at our institution and patient informed consent. All IS agents except MTX were discontinued one month prior to the start of treatment. Prednisone dose was adjusted to 0.5 mg/kg/day and decreased by 5 mg/day every week in the absence of posterior pole inflammation. Three doses of 5 mg/kg infliximab were administered IV at weeks 0, 2, and 6. Visits including a full ophthalmological assessment took place at weeks 1, 3, 4, 5, 7, 8, and 12; fluorescein angiographies (FAG) and retinograms were performed at baseline and week 16.

RESULTS. No adverse effects, and no ocular or systemic exacerbations were observed. Final prednisone dose was less than 7.5 mg for six patients, and 15 mg for no. 2.

Visual acuity* Vitreous haze

Patients Diagnosis Posterior pole Baseline Week 12 Baseline Week 12

1 Behcet dis. Vasculitis 20/25 20/25 0 0

2 Behcet dis. Vasculitis 20/32 20/28 0

3 Behcet dis. Vasculitis 20/32 20/28 0

4 Behcet dis. Vasculitis 20/125 20/100 2+

5 Behcet dis. Vasculitis 20/200 20/100 2+

6 Sarcoidosis Vasculitis 20/40 20/28 2+

7 Multifocal choroiditis Chorioretinitis CF CF 1+ 1+

*best response eye

Measurable improvement of visual acuity was documented in patients 2, 3, 4, 5, and 6. FAGs and retinograms confirmed vitreous clearance in all patients, and disappearance of a macular edema (which had been present for years) in patient 5. Only patient 7, with chronic multifocal choroiditis, had no improvement.

CONCLUSION. In this preliminary open trial, infliximab treatment appears to be a useful option in the short term for the management of refractory PU patients with retinal vasculitis

 

PENTOXIFYLLINE USE FOR BEHCETS DISEASE:A FOLLOW-UP COHORT STUDY.

Elizabeth M Chang, George C Liang Chicago, IL

Purpose: Previously we reported our favorable experience with the use of pentoxifylline in the treatment of recurrent oral and vaginal ulcers in patients with Behcets disease, now we report the follow-up results of our cohort.

Methods: An outpatient chart review was performed to verify the efficacy, the duration of effect and side effects with the use of pentoxifylline in our outpatient clinic patients with Behcets (on the 4 limited Behcets and 3 complete Behcets patients who we previously reported and on additional 5 patients- 3 with complete and 2 with incomplete Behcets disease).

Results: All patients were placed on at least 400mg PO QD of pentoxifylline. 9/12 of patients experienced decreased frequency or complete resolution of their vaginal and oral ulcers. 2/6 complete disease patients had complete resolution of their vaginal and oral ulcerations without recurrence documented for 8-29 months. One of them was also taking colchicine. Another complete Behcets patient initially experienced complete resolution of both oral and genital ulcerations but experienced one episode of oral ulcer recurrence while battling with multiple flares of manifestations of neuro-Behcets in the last year. Complete resolution of oral and vaginal ulcers occurred in one of the limited Behcets patients with QID pentoxifylline dosing. In the limited Behcets patients, 3/6 reported decreased frequency of ulcer recurrence and 1/6 had a partial response for 4 months then discontinued the medication for lack of further efficacy without subsequent exacerbation of her disease. The side effects experienced were diarrhea and peripheral neuropathy. One of the patients with diarrhea and the patient with peripheral neuropathy discontinued therapy secondary to the side effects. One limited Behcets patient had reversible diarrhea with dose adjustment then ulcer improvement in combination with colchicine.

Conclusion: Overall, Pentoxifylline has continued to be over 50% effective for the treatment of oral and vaginal ulcerations our patients with Behcets disease for up to 29 months. In fact, the data suggests that pentoxifylline appears to maintain its efficacy with long-term use and to be synergistic in combination with colchicine.

 

ANTIPHOSPHOLIPID ANTIBODIES IN PATIENTS WITH BEHCET'S DISEASE IN OMAN.

M H Al-Maini, E M El-Ageb, Y M Al-Farsi, E R Richens Sultanate of Oman and Toronto, Canada

The clinical features of Behcet's disease (BD) were studied in 33 patients from the Sultanate of Oman. The prevalence of symptoms was: recurrent oral ulcers, 100%; arthritis/arthralgia, 73%; genital ulceration, 73%; folliculitis, 64%; neurological lesions, 61%; retinal vasculitis, 30%; iritis and hypopyon, 24%; gastrointestinal lesions, 12%; venous thrombosis, cardiovascular lesions, pleuropulmonary lesions and fever, each 6%.

APL (both anticardiolipin antibodies [ACAs] and anti-b2 glycoprotein I antibodies [ab2GPIs]) were present in 10/33 (30%) of the BD patients and in 54/73 (74%) of SLE patients (c2 =21.2, p < 0.001). In APL positive patients, 32/54 SLE patients and 1/10 BD patients possessed both ACA and abGPI antibodies, both IgG and IgM isotypes (c2 = 7.2, p< 0.01). 2 other patients possessed both antibodies, 1 IgG and the other IgM isotype. 6 further patients possessed ab2GPI antibodies, 4 the IgM isotype, 1, the IgG isotype and 1 both IgG and IgM isotypes; the remaining 1 possessed IgG ACA only. In the clinical ranges, there was no significant difference in mean antibody levels between BD and SLE patients.

In individual BD patients, there was no apparent association of APL antibodies with clinical features of disease. For the cohort, there was no significant difference in the frequency of organ involvement between patients with and without APL antibodies. This study has not demonstrated a pathognomonic role for APL antibodies in BD.

 

BEHCET DISEASE ASSOCIATED WITH SEVERE GASTROPARESIS: A DRAMATIC RESPONSE TO COMBINATION THERAPY WITH METHOTREXATE AND INFLIXIMAB.

Richard Bertken Fresno, CA

Introduction: Behcet disease (BD) is an idiopathic, multisystem immune-mediated inflammatory disorder. The most prominent clinical manifestation is the formation of oral ulcers, accompanied by one of the following: genital ulcers, uveitis, cutaneous or large vessel inflammation, skin lesions, arthritis, and meningoencephalitis. Infliximab is a chimeric monoclonal antibody directed against TNFa that has been used successfully in the treatment of other inflammatory disorders, including rheumatoid arhtritis and Crohn's disease. We report on a patient whose BD symptoms dramatically improved following therapy with infliximab.

Case Report: A 43-year-old woman experienced gradual progression over eight years of episodic aphthous ulcerations (oral and genital) linked to inflammatory arthralgias, fevers, rashes, and headaches. For eighteen months she noted progressive anorexia, nausea, vomiting, and weight loss. Several episodes of vomiting resulted in hospitalization for volume repletion. Radionuclide gastric emptying studies showed severe gastroparesis. Progressive inanition (with 35% loss of body weight) was addressed by the insertion of a jejunostomy feeding tube. Prednisone moderated the arthralgia-fever-ulcer-rash syndrome, and a clinical diagnosis of Behcet disease was made. The co-morbidity of gastroparesis could not be attributed to Behcet on the basis of precedent in the medical literature, but the possibility of an immuno-inflammatory origin for the life-threatening gastroparesis led to the decision to implement combination anti-rheumatic therapy with infliximab 300 mg every 8 weeks, methotrexate 20 mg SQ weekly, and dapsone 75 mg daily. There was a rapid, dramatic improvement in all symptoms, allowing the withdrawal of prednisone; within 4 months the only residual symptom was minor flaring of ulcers toward the end of the 8 week dosing cycle of infliximab. Over six months her body weight returned to her pre-morbid level, and the jejunostomy tube was removed. Repeat gastric emptying studies were normal. At eleven months of follow-up, the patient remains asymptomatic on the same treatment regimen.

 

VALIDATE THE EFFICIENCY OF THE APPLICATION OF A DIAGNOSTIC PROTOCOL BASED ON THE PATTERNS OF PRESENTATION OF UVEITIS.

Gema Bonilla, Santiago Munoz-Fernandez, Ventura Hidalgo, Julia Fernandez-Melon, Armel Schlincher, Ana Fonseca, Fernando Gamero, Begona Damas, Emilio Martin-Mola Madrid, Madrid, Spain

Objectives: To validate the efficiency of the application of a diagnostic protocol based on the patterns of presentation of uveitis to establish the diagnosis.

Methods: Our Uveitis Clinic consists on a multidisciplinary team of Ophtalmologists and Rheumatologists. We defined a clinical diagnostic protocol for the uveitis, based on the frecuency of syndromes found in the literature in each clinical patterns of uveitis and the symptoms of the patients. We routinarelly performed a careful history, a complete ophthalmologic examination. If the uveitis was not an pure opthalmologic syndrome we performed hemogram, biochemistry, ESR, a fluorescent treponemal antibody absortion test, an urinary test and a chest X Ray. Other diagnostic procedures were ordered according to a established protocol based on the clinic patterns of presentation of uveitis.Patients data were prospectively recorded from June 1997 to October 2000.

Result: 376 patients were included.We have achieved a definitive diagnosis of the uveitis in 56.6%. 70 (21%) had some type of spondyloarthropaty (30 patients were diagnosed in our uveitis clinic), 33 uveitis (9.8%) were secondary to infections (23 herpes, 6 toxoplamosis, 3 tuberculosis, 1 candida), 3 (0.89%) were masquerade syndromes (1 lung cancer and 2 lymphoproliferative diseases), 9 (2.67%) were traumatic, 47 ( 14 %) were ophtalmologic syndromes, 21(6,25 %) uveitis were secondary to other rheumatic diseases ( 8 Behcet disease, 8 sarcoidosis, 4 Sjogren syndrome and one juvenile chronic arthritis), 2 were tubulointersticial nepritis associated with uveitis (TINU syndrome), 1 multiple sclerosis, 146( 43.4%) were diagnosed of idiopathic uveitis and 44 of them were lost during the follow-up.Conclusion: We have achieved the etiology of the uveitis in 56.6 % a greater percentage than those found in other series in which the diagnostic procedures have not been prestablished. In addition, it could have a better cost- effective impact and avoid the number of consultations between different specialist. We believe that this is the first study in which a clinical protocol of diagnostic procedures has been validated in patients with uveitis.

 

OCULAR INVOLVEMENT IN BEHCET DISEASE. A MULTICENTER REPORT.

Paolo Picco, Riccardo De Marco, Marco Gattorno, Antonella Buoncompagni, Maria Bardare, Fernanda Falcini, Paolo Vittone, Loredana Lepore, Alberto Martini Genoa, Milan, Florence, Trieste and Pavia, Italy

Tuesday, November 13, 2001, 7:30 AM, Poster Session: Miscellaneous Rheumatic Diseases of Children (7:30 - 9:00 AM) Board Number: 30 Exhibit Hall D and E, Moscone

Behcet disease (BD) is a systemic vasculitis characterized by prominent mucocutaneous lesions (e.g. oral and/or genital aphthae, folliculitis, pseudo-folliculitis, pathergic reaction), inflammatory eye diseases and additional inflammatory diseases which include, for example, musculoaskeletal (e.g. myalgias, non erosive arthritis), gastrointestinal and renal diseases. Juvenile BD (jBD) is uncommon (1.5-3% out the whole BD population), indolent, with a relapsing-remitting course. Furthermore significant phenotypical differences are reported between one series and another. We report the prevalence of ocular involvement of the first Italian nation-wide survey on JBD. Patients and methods. We collected a series of jBD patients during the period between January 1997 and December 2000. A questionnaire was mailed to the Paediatric Rheumatologic Units and to the Paediatric Departments in Hospital of secondary degree care. We included both jBD patients with complete and incomplete form according to ISG and Krause definitions. We ruled out non Italian patients in order to obtain a homogeneous series. Results. Forty-nine patients (38 males and 11 females) with jBD were collected. Their mean age at the moment of the last consultation was 14.6 years (range 7 to 36 months). Out of them 29 patients developed the complete form of jBD. Eye inflammatory involvement was disclosed in 4 pts with incomplete form and in 16 pts with the complete form of jBD (50% of the whole series). Posterior uveitis associated with pars planitis was found in 1 pt with the incomplete form and in 7 pts with jBD complete form. Posterior uveitis developed into a diffuse inflammation of the uvea (panuveitis) in 5 patients. Anterior uveitis associated with hypopion was present in 1 pt affected with the incomplete form. Other ocular diseases were present as well as papilloedema which was found in 7 (14%) pts, retinal vasculitis in 3 (6%) pts, and episcleritis in 1 (2.5%) patient. An ulcerative keratoconjuinctivitis remained the heralding symptom in 1 pt who developed an incomplete jBD form, for a long time. Furthermore an abnormal inflammatory reaction leading to a severe, hypertensive glaucoma during non-invasive laser surgical treatment for cataract occurred in 2 pts; this finding might be interpreted as a tissue pathergic reaction. Notably in 8 pts with posterior uveitis or retinal vasculitis developed severe sighting loss (16%). In the following table the prevalence of eye diseasese in Italian and non Italian series are reported. Conclusions. Eye involvement is common also in Italian jBD patients, even if its prevalence is reduced in comparison with Eastern people (see table). In our experience it is more severe in the complete form of jBD thus it may lead to blindness. Although therapeutic schedules have not been validated, surgical treatment should be avoided.

Our series ('01) Kone' Paut ('99) Eldem ('98) Al Dalaan ('94) Shimizu ('79)

50%             61%                80%            56%            90%

 

LONG-TERM OUTCOME OF VISION IN BEHCET'S DISEASE.

Fereydoun Davatchi, Farhad Shahram, Hormoz Chams, Abdolhadi Nadji, Ahmad-Reza Jamshidi, Cheyda Chams, Mahmood Akbarian, Farhad Gharibdoost Tehran, Islamic Republic of Iran

INTRODUCTION: The natural history of ocular lesions in Behcet's Disease (BD) is gradual progressions of lesions toward severe loss of vision or blindness. The association of cytotoxic drugs and steroids has dramatically changed the outcome. However, some authors still believe that the improvement is temporary and in the long run (10 years) the eyes progress toward blindness no matter what treatment was applied. The aim of this study was to address this issue by evaluating the visual acuity (VA) in patients with more than 10 years of ocular manifestations. The outcome was then compared with patients having eye lesions for less than 5 years.

MATERIALS AND METHODS: From our database all patients having posterior uveitis and/or retinitis, and having received cytotoxic drugs (cyclophosphamide, methotrexate, chlorambucil, azathioprine, cyclosporine A) were selected. They were divided upon the duration of their eye lesions to 3 groups. Group 1: Less than 5 years from the onset of their eye lesions. Group 2: Between 5 and 10 years. Group 3: More than 10 years. VA of the first and the last visit were compared in each group by the Student paired t test. Then the 3 groups were compared to each other to find if the duration of the disease had any effect on the outcome of the VA.

RESULTS: Data from 959 patients were included in the study. Group 1 comprised 648 patients. The mean duration of the eye disease (MDED) was 32.2 months. The mean VA improved from 4/10 to 5/10 (t=9.665, p<0.0001), 71% of the eyes were improved or stabilized while 29% were aggravated, the confidence interval (CI) was 2.8. Group 2 comprised 182 patients. The MDED was 84.2 months, the mean VA improved from 3.5/10 to 4.1/10 (t=3.405, p<0.001), 69% of the eyes were improved or stabilized while 31% were aggravated (CI=5.1). Group 3 comprised 68 patients. The MDED was 165.6 months, the mean VA improved from 3/10 to 3.9/10 (t=1.568, p=0.12), 69% of the eyes were improved or stabilized while 31% were aggravated (CI=8.4)

CONCLUSION: Visual acuity aggravated only in approximately 1/3 of the eyes regardless of the duration of the disease. However, longer duration caused a lower VA at the baseline and subsequently at the end of the study, while the mean improvement remained the same for all groups. Therefore, the majority of eyes do not progress toward blindness, even in long run, if appropriately treated.

 

FREQUENCY OF IL-12 RECEPTOR BEARING T CELLS IS A SIMPLE MARKER TO MONITOR THE DISEASE ACTIVITY IN BEHCET'S DISEASE.

Mitsuhiro Takeno, Hiroko Nagafuchi, Noboru Suzuki, Takahide Matsuda, Tsuyoshi Sakane Kawasaki, Kanagawa, Japan

There is accumulating evidence that preferential activation of Th1 cells is involved in clinical exacerbation of Behcetfs disease. The Th1 polarization is associated with an increased plasma level of IL-12 and excessive IL-12 synthesis by peripheral mononuclear cells (PBMC) in BD patients. Because there are qualitative and quantitative differences in IL-12 receptor and responsiveness to IL-12 between Th1 and Th2 cells, we here studied expression of IL-12 receptor (IL-12R) on peripheral T cells in patients with BD.

We used a monoclonal antibody, TOS, which recognizes the conformational epitope of IL-12R in this study. IL-12R positive T cells expressed mRNA of Th1-related proteins such as T-bet, Txk, and IL-12R beta 2 chain and secreted large amounts of IFN-gamma when compared with IL-12R negative cells, indicating that TOS preferentially recognizes Th1 cells.

Flowcytometric analysis revealed that IL-12R positive cells in circulating T cells was significantly higher in active BD patients (43.9+7.9%, mean+SEM) than healthy controls (12.9+0.9%), inactive BD patients (11.3+2.5%), and RA patients (14.8+3.6%). Concordantly, expression of Th1-related proteins and IFN-gamma produced by PHA and PMA-stimulated T cells were also higher in active BD patients than any other groups. A longitudinal study of individual patients showed that IL-12R expressing T cells as well as IFN-gamma production were increased in acute attacks of symptoms and decreased during remission. Thus, increased IL-12R expressing cells are closely associated with Th1 polarization during clinical exacerbations.

Collectively, IL-12R expression is a simple marker to monitor the disease activity of BD and the IL-12/IL-12R system is a possible therapeutic target of the disease.

 

 

ENHANCED EXPRESSION OF CHEMOKINES IN BEHCETS DISEASE.

Sung-Hwan Park, Mi-La Cho, Myung-Soo Lee, Kyung-Soo Park, Young-Il Seo, Wan-Uk Kim, Jun-Ki Min, Chong-Hyeon Yoon, Youn-Sik Hong, Chul-Soo Cho, Ho-Youn Kim Seoul, Republic of Korea

Objective: To investigate the chemokine expression in patients with Behcets disease (BD) and to access the usefulness of circulating chemokine levels as the disease activity marker. Methods: C-X-C chemokine (IL-8) and C-C chemokines (RANTES, MIP-1a, and MCP-1) were measured by ELISA in sera and culture supernatants of peripheral blood mononuclear cells (PBMC) obtained from patients with BD and healthy controls (HC). Supernatants were collected from PBMC culture unstimulated or stimulated with interferon gamma for 72 hr. The activity of the disease was clinically evaluated by the number of actively involved organ systems registered on the day of blood sampling. Results: The serum levels of C-X-C and C-C chemokines were significantly higher in patients with BD (n=67) than in age and sex matched HC (n=44) (p<0.001 for all chemokines). Also, increased IL-8 serumlevels were found in patients with active disease (n=21) compared to inactive disease (n=46)(305.6 +/- 88.6 versus 245.6+/- 90.7 pg/ml, p=0.020). Patients with active disease showed higher circulating levels of C-C chemokines than those with inactive disease, but differences did not reach statistical significance. The serum levels of IL-8 strongly correlated with C-C chemokine levels (MIP-1a, r=0.444, p<0.001; RANTES, r=0.475, p<0.001; MCP-1, r=0.464, p<0.05) and serum levels of IL-15 (r=0.555, p=0.005). The chemokine productions by interferon gamma-stimulated PBMC were significantly augmented in BD (n=25) compared to healthy controls (n=11) (p<0.05 for all chemokines). Futhermore, the IL-8 production was more enhanced in active stage of BD (n= 8) than those with inactive stage (n= 17) (266.2 +/- 115.0 versus 175.3 +/- 61.9 pg/ml, p= 0.027). Conclusion: Circulating levels of both C-X-C and C-C chemokines are elevated in BD, which seems to be related with increased production of chemokines by PBMC in response to interferon gamma. Serum levels of chemokines, especially, IL-8 may be a useful marker of disease activity in BD.

 

ENHANCED PRODUCTION OF IL-15 IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM PATIENTS WITH BEHCETS DISEASE IN RESPONSE TO HUMAN HEAT-SHOCK PROTEIN 60.

Kyung-Su Park, Myung-Soo Lee, Chong-Hyeon Choi, Jin-Jung Choi, Wan-Uk Kim, Do-June Min, Yeon-Sik Hong, Jun-Ki Min, Sung-Hwan Park, Chul-Soo Cho, Ho-Youn Kim Seoul, Republic of Korea

OBJECTIVE : Heat-shock protein is thought to act as an self-antigen in Behets disease (BD) and IL-15 is a growth factor for gd T cell which is known to be deeply involved in BD. We tried to evaluate the effect of human heat-shock protein 60 on the production of IL-15 by peripheral blood mononuclear cells (PBMCs) from patients with Behets disease. PATIENTS and METHODS : We stimulated PBMCs from BD patients (n=12) and healthy controls (n=12) with 10 mg/ml of recombinant human heat shock protein 60 (rhHSP60), 10 mg/ml of LPS and 5 mg/ml of PHA, and then measured IL-15 level in culture supernatants. Serum levels of IL-15 and IL-12 were also determined by ELISA in BD patients (n=31) and healthy controls (n=34). BD patients were divided into active (n=16) and inactive (n=15) groups according to clinical manifestations and the differences in serum IL-15 and IL-12 levels between two groups were studied. RESULTS : The production of IL-15 from PBMCs was increased in response to rhHSP60, LPS, and PHA in BD patients and healthy controls compared to unstimulated PBMC. rhHSP60-stimulated IL-15 production was higher in BD patients than in healthy controls (132.5 26.0 versus 82.0 23.8 pg/ml, P < 0.05), whereas neither LPS- nor PHA-stimulated IL-15 production make any difference between the two groups. Additionally, the serum levels of IL-15 and IL-12 were higher in BD patients than in healthy controls (IL-15 ; 115.0 53.9 pg/ml vs. 57.9 27.2 pg/ml, P < 0.01, IL-12 ; 92.2 72.4 pg/ml vs. 50.0 48.9 pg/ml, P < 0.05 ). The serum level of IL-15 and IL-12 tended to be higher in active BD group compared to inactive BD group. CONCLUSION : Our data suggest that elevated IL-15 production may be involved in the pathogenesis of BD, which is probably mediated by HSP 60.

 

INFLUENCE OF INTERFERON (IFN) a TREATMENT ON ALTERED LYMPHOCYYTE SUBPOPULATIONS IN BEHCET`S DISEASE (BD)- A PILOT STUDY.

Michaela Treusch, Nicole Stuebiger, Ilhan Guenaydin, Christopher C Amberger, Silvia Koch, Lothar Kanz, Manfred Zierhut, Ina Koetter Tuebingen, Germany

Introduction:In Behcet`s Disease, a systemic leukocytoclastic vasculitis of unknown origin, standard treatment comprises immunosuppressive drugs. We successfully treated 50 patients with BD with IFN-a2a which is surprising, because it is immunostimulatory and induces autoimmune diseases such as SLE and RA. The aim of this study was to evaluate the immunomodulatory effects of IFN-a2a in BD.

Materials and methods:Nine patients with BD were examined before and under IFN treatment (6 Mill. iU daily, maintenance dosage 3 Mill. iU 3x/week) together with 5 healthy age and sex matched controls. PBMC were stained with monoclonal antibodies (CD3, CD4, CD8, CD16, CD56, CD19, CD20, CD14, CD45RA/RO, CD25, ab,gd-T-cell-receptor), conjugated with four colour (FITC, PE, PerCP, APC) fluorescent dyes and measured by FACS (Becton Dickinson). Statistical analysis was performed by Wilcoxon rank test.

Results:All patients entered complete remission. Compared to the controls, CD8+gd+ T-cells were elevated (median 8,5% (range 1,9-12,3%), controls median 1,8% (range 0,9-11%), ns), as were CD4+RO+RA- T-cells (median 23,5% (0,2-58,4%) vs. controls median 18,8% (7,1-22,7%), ns), and NK cells (CD16/56+) (median 12,8% (4,7-15,4%), controls median 3,3% (1,8-21,1%), ns). CD4+RO-RA+ T-cells (median 26,6% (1-56,5%), controls median 46,3% (36,4-71,9%), p=0,016) were lowered. Under IFN-a, CD8+gd+ T-cells decreased (median 8,5% (1,9-12,3%), week 24 median 5,9% (0,9-7,6%), ns), as did NK cells (median 12,8% (4,7-15,4%), week 24 median 6,1% (1,6-10,7%), p=0,06, ns). B cells (CD19/20) and monocytes (CD14) rose (median 22,1% (7-44%), week 4 median 31,4% (10-55%), ns).

Discussion:Compared to healthy controls, there was a clear tendency towards higher numbers of NK-cells and CD8+gd+ T-cells which decreased under IFN-a treatment. This did not reach significance due to the small sample size. Naive CD4+RA+ T-cells were significantly lowered in the patients, but remained unchanged. This implicates a participation of NK cells and CD8+gd+ T-cells in the pathogenesis of BD and may be one mechanism by which IFN-a exerts its therapeutic effects. The IFN-a induced elevation of B cells and monocytes could explain some of the side effects as autoimmune phenomena. Further analysis on larger patient and control groups is under way.

 

 

POLYMORPHISMS IN THE ENDOTHELIAL NITRIC OXIDE SYNTHASE GENE ASSOCIATED WITH BEHCET'S DISEASE.

Jumana A Karasneh, Ahmet Gul, Ali H Hajeer, Jane Worthington, William ER Ollier Manchester, United Kingdom and Istanbul, Turkey

Wednesday, November 14, 2001, 12:30 PM, Poster Session: Vasculitis - Pathophysiology (12:30 - 2:00 PM) Board Number: 107 Exhibit Hall D and E, Moscone

Background : Behcet's disease (BD) is a recurrent acute systemic vasculitis with a chronic course and unknown cause. A major feature of BD is endothelial damage resulting from high levels of oxygen superoxides and intermediates produced by neutrophils. Endothelial nitric oxide (eNO) is a potent vasodilator and inhibitor of monocyte and platelet adhesion, produced enzymatically from L-arginine by nitric oxide synthase (NOS). The -786 TC polymorphism in eNOS promoter has been reported to reduce activity in a reporter gene assay, and the 27bp VNTR in intron 4 has been associated with reduced circulating NO levels.

Aim : To investigate the role of eNOS gene polymorphisms in BD.

Methods: A case control study was carried out using 160 Turkish BD patients fulfilling the international study group (ISG) criteria and 105 healthy Turkish controls. Fifty six of the cases have a family history of BD. The -786 TC polymorphism and the 894 G T polymorphism in exon 7 were genotyped by PCR-RFLP using MspI and BanII restriction enzymes respectively. The 27 bp VNTR ((a) allele is 4 repeat and (b) allele is 5 repeat) was genotyped using PCR and agarose gel electrophoresis.

Results:

-786 TC Genotype frequency 27bp VNTR Genotype frequency

(n) (n)

TT TC CC bb ba aa

BD families 70% (39) 29% (16) 2% (1) 88% (44) 10% (5) 2% (1)

BD cases 54% (84) 41% (64) 6% (9) 77% (115) 22% (33) 1% (2)

Controls 42% (43) 43% (44) 15% (15) 64% (66) 33% (34) 3% (3)

Significant differences were found between cases and controls in eNOS -786 polymorphism for allele (p =0.01) and genotype frequencies (p=0.02). More significant results were obtained when family history was taken in consideration (p = 0.0002, 0.001) for allele and genotype frequencies and for the intronic marker (p = 0.0047, 0.003 respectively). No difference in allele and genotype frequencies were found between cases and controls in the exonic marker. Haplotype investigation revealed that both the promoter and the intronic markers are in linkage disequilibrium and the TTbb genotype is significantly higher in patients than controls (p<0.00001 ).

Conclusion: The eNOS gene promoter and intronic markers are associated with BD. Individuals having the genotype *TT -786 / *bb VNTR are at higher risk to develop BD (OR =2.6, 95%CI (1.53-4.48)).

 

MEFV MUTATIONS ARE INCREASED IN BEHCET S DISEASE (BD) AND ASSOCIATE WITH VASCULAR INVOLVEMENT.

Pamir Atagunduz, Tulin Ergun, Haner Direskeneli Istanbul, Turkey

Introduction: Mutations of the MEFV gene, which encodes the neutrophil protein pyrin (marenostrin) was recently linked to familial Mediterranean fever (FMF), an autosomal recessive, periodic inflammatory disease. The association of MEFV mutations with BD, a systemic vasculitic disorder suggested to have a neutrophil hyperfunction, was also reported. The role of MEFV mutations in the pathogenesis of BD was further investigated in a population with high frequencies of both disorders.

Methods: We screened a cohort of 50 BD patients for M694V, M680I and V726A mutations with ARMS method using PCR. All patients fulfilled the international criteria for BD and have been screened for a possible diagnosis of FMF with revised Tel-Hashomer criteria. The results were compared to a non-inflammatory control group (n=186).

Results: MEFV mutations were found in 24% (12/50) of BD patients compared to 9.1% (17/186) of the controls (p=0.008)(M694V in 9, V726A in 3 and M680I in one patient). All patients were heterozygous for MEFV mutations except for one patient homozygous for M694V. Out of 12 BD patients with MEFV mutations, 8 had vascular involvement compared to 5 patients in the mutation-negative group (p=0.0007). Four out of 13 patients with vascular involvement had severe vascular complications such as Budd-Chiari syndrome, vena-cava superior thrombosis and vascular neuro-BD, all in mutation-positive group (p=0.002). Patergy test was also more frequently positive in the MEFV mutation group (10/12 vs 16/35, p=0.04), whereas the frequency of uveitis did not differ in both groups (4/12 vs 8/38, p=0.45).

Conclusion: MEFV mutations, especially M694V, may act as genetic susceptibility factors in BD. The association of only vascular manifestations, but not uveitis with MEFV mutations also suggests that neutrophil-related genetic predispositions might be linked to certain clinical subsets of BD.