OBJECTIVES: To analyze arthritic manifestations in Behcet disease, which is one of the most common manifestations of Behcet disease. METHODS: Among the patients who visited the Rheumatology Division, Keimyung University Dongsan Medical Center, Taegu, Korea from March 1997 to February 1998, 35 patients, with more than 3 months follow-up, were compatible for the diagnosis of Behcet disease according to the Shimizu criteria, after exclusion of uncertain or possible Behcet cases. The presence of various manifestations was evaluated. Regarding the joint manifestations, the involved joint, signs and the pattern of the articular symptoms were examined. Basic laboratory tests, HLA studies and simple radiologic studies were done. RESULTS: All 35 patients had evident, recurrent, painful oral ulcers by the study definition. Genital ulcers were found in 29%, skin lesions in 77%, uveitis in 9%, gastrointestinal ulcerations in 6% and vascular manifestations in 6%. Joint manifestations appeared in 97%. Knee(91%), proximal interphalangeal (53%) and metacarpophalangeal joints(21%) were the main sites. Tenderness was prominent in 91% and swelling in 44%. Polyarticular presentation was found in 47%. In most cases (76.4%), the articular symptom was short-lasting. C-reactive protein was likely to be positive in active Behcet disease. HLA B51 was positive in 46%. CONCLUSIONS: In Behcet disease, various manifestations can be found. The arthritic manifestation seems quite common. It may present as seronegative rheumatoid arthritis. Otherwise, it may present as palindromic rheumatism.
Adult ; Arthritis, Rheumatoid/diagnosis* ; Arthritis, Rheumatoid/blood ; Behcet's Syndrome/diagnosis* ; Behcet's Syndrome/blood ; C-Reactive Protein/metabolism ; Comparative Study ; Diagnosis, Differential ; Female ; Human ; Joints/pathology ; Male ; Middle Age ; Rheumatic Diseases/diagnosis* ; Rheumatic Diseases/blood

High-mobility group box 1 (HMGB1) protein has been demonstrated to play an important role in chronic inflammatory diseases including rheumatoid arthritis, and systemic lupus erythematosus. This study investigated the association between extracellular HMGB1 expression and disease activity, and clinical features of Behcet's disease (BD). Extracellular HMGB1 expression in the sera of 42 BD patients was measured and was compared to that of 22 age- and sex-matched healthy controls. HMGB1 expression was significantly increased in BD patients compared to healthy controls (78.70 +/- 20.22 vs 10.79 +/- 1.90 ng/mL, P = 0.002). In addition, HMGB1 expression was significantly elevated in BD patients with intestinal involvement compared to those without (179.61 +/- 67.95 vs 61.89 +/- 19.81 ng/mL, P = 0.04). No significant association was observed between HMGB1 concentration and other clinical manifestations, or disease activity. It is suggested that extracellular HMGB1 may play an important role in the pathogenesis of BD.
Adult ; Aged ; Behcet Syndrome/genetics/*metabolism/pathology ; Extracellular Space/metabolism ; Female ; HMGB1 Protein/genetics/*metabolism ; Humans ; Inflammation ; Intestinal Diseases/blood/genetics ; Male ; Middle Aged ; Young Adult

Behcet's disease (BD) is a chronic inflammatory disorder of unknown aetiology, and recognised as a multi-system vasculitis. It has been postulated that an imbalance of the oxidant and antioxidant systems related to the disease are important in its pathogenesis. Previous publications have reported increased levels of enzymatic antioxidant defence systems in patients with BD. The non-enzymatic antioxidant systems, including vitamin C and uric acid, were looked for in the present study. For this aim, the serum malondialdehyde (MDA), an end product of lipid peroxidation, and vitamin C and uric acid, as endogenous antioxidants, were determined in 20 patients with BD (11 in active and 9 in inactive periods) and 20 healthy subjects. The MDA level was significantly higher in both the active and inactive period patients compared with the control group (p < 0.001, p < 0.05, respectively). The MDA level was also significantly higher in the active period patients compared with the inactive period patients (p < 0.05). The vitamin C levels were significantly lower in both the active and inactive period patients compared with the control group (p < 0.001, p < 0.05, respectively). There was no significant difference in the vitamin C level between the active and inactive period patients (p > 0.05). There was also no significant difference in uric acid levels between the groups (p > 0.05). In the patients group, a negative correlation was found between the levels of serum MDA and vitamin C (r=-0.517; p < 0.05). Our results indicate that decreased vitamin C and increased MDA levels reflect the increased levels of oxidative stress in BD patients, and this situation may be important in relation with its pathogenesis.
Adenosine Deaminase/metabolism ; Adult ; Ascorbic Acid/*blood ; Behcet Syndrome/*blood ; Blood Sedimentation ; Female ; Human ; Lipoproteins, LDL/blood ; Male ; Malondialdehyde/blood ; Middle Aged

PURPOSE: The serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have recently been shown to be correlated highly with disease activity in patients with intestinal Behcet's disease (BD). However, it remains unclear whether sTREM-1 levels reflect endoscopic activity in intestinal BD. This study aimed to evaluate the correlation of sTREM-1 levels with endoscopic activity in intestinal BD. MATERIALS AND METHODS: A total of 84 patients with intestinal BD were enrolled. Endoscopic activity was compared with sTREM-1 levels as well as other laboratory findings, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). RESULTS: sTREM-1 levels were significantly increased in intestinal BD patients compared with controls (37.98+/-27.09 pg/mL vs. 16.65+/-7.76 pg/mL, p=0.002), however, there was no difference between endoscopically quiescent and active diseases (43.53+/-24.95 pg/mL vs. 42.22+/-32.68 pg/mL, p=0.819). Moreover, serum sTREM-1 levels did not differ in terms of number, shape, depth, size, margin, or type of ulcer in patients with intestinal BD. However, mean ESR and CRP levels in patients with active disease were significantly higher than those in patients with quiescent disease (p=0.001, p<0.001, respectively). In addition, endoscopic activity scores for intestinal BD were correlated significantly with both CRP levels (gamma=0.329) and ESR (gamma=0.298), but not with sTREM-1 levels (gamma=0.166). CONCLUSION: Unlike CRP levels and ESR, serum sTREM-1 levels were not correlated with endoscopic activity in patients with intestinal BD.
Adult ; Behcet Syndrome/*blood/*pathology ; Biological Markers/blood ; Blood Sedimentation ; C-Reactive Protein/metabolism ; Female ; Humans ; Intestinal Diseases/*blood/*pathology ; Male ; Membrane Glycoproteins/*blood ; Receptors, Immunologic/*blood

PURPOSE: Behcet's disease (BD) is a disease of unknown etiology, which has multisystemic involvement. This multisystemic involvement might be the clue for an autoimmune pathogenesis. In order to evaluate an autoimmune pathogenesis, we examined immunoreactans depositions in the skin of BD patients. MATERIALS AND METHODS: The skin samples of 108 BD patients (28 perilesional skin, 44 positive pathergy test site, 22 negative pathergy test site, 14 normal skin) were examined for the depositions of immunoglobulin (Ig)M, IgG, IgA, complement 3 (C3), and fibrinogen (F) using direct immunofluorescence (DIF). The data were statistically compared to the DIF of 36 systemic lupus erythematosus (SLE) patients and 20 healthy controls using chi-square Fisher exact test. RESULTS: Highly significant immunoreactans depositions were obtained in BD (deposition rates: IgM 70.3%, IgG 0%, IgA 20.3%, C3 62.9%, F 83.3%). The comparison with SLE revealed no differences in IgM, IgA, and C3. However, IgG deposition was higher in SLE while F deposition was higher in BD. In both BD and SLE, the Ig depositions were highly significant when the data were compared with the healthy controls. CONCLUSION: The significant deposition of immunoreactans in BD, especially in the negative pathergy and the normal skin sites, were observed. This study is the first controlled study revealing positive Ig depositions in BD, and it is expected to help us to reconsider the autoimmune pathogenesis in BD.
Adolescent ; Adult ; Aged ; Behcet Syndrome/*metabolism ; Case-Control Studies ; Female ; Fluorescent Antibody Technique, Direct/*methods ; Humans ; Immunoglobulin A/metabolism ; Immunoglobulin G/metabolism ; Immunoglobulin M/metabolism ; Male ; Middle Aged ; Skin/metabolism/pathology ; Young Adult

PURPOSE: Behcet's disease (BD) is a disease of unknown etiology, which has multisystemic involvement. This multisystemic involvement might be the clue for an autoimmune pathogenesis. In order to evaluate an autoimmune pathogenesis, we examined immunoreactans depositions in the skin of BD patients. MATERIALS AND METHODS: The skin samples of 108 BD patients (28 perilesional skin, 44 positive pathergy test site, 22 negative pathergy test site, 14 normal skin) were examined for the depositions of immunoglobulin (Ig)M, IgG, IgA, complement 3 (C3), and fibrinogen (F) using direct immunofluorescence (DIF). The data were statistically compared to the DIF of 36 systemic lupus erythematosus (SLE) patients and 20 healthy controls using chi-square Fisher exact test. RESULTS: Highly significant immunoreactans depositions were obtained in BD (deposition rates: IgM 70.3%, IgG 0%, IgA 20.3%, C3 62.9%, F 83.3%). The comparison with SLE revealed no differences in IgM, IgA, and C3. However, IgG deposition was higher in SLE while F deposition was higher in BD. In both BD and SLE, the Ig depositions were highly significant when the data were compared with the healthy controls. CONCLUSION: The significant deposition of immunoreactans in BD, especially in the negative pathergy and the normal skin sites, were observed. This study is the first controlled study revealing positive Ig depositions in BD, and it is expected to help us to reconsider the autoimmune pathogenesis in BD.
Adolescent ; Adult ; Aged ; Behcet Syndrome/*metabolism ; Case-Control Studies ; Female ; Fluorescent Antibody Technique, Direct/*methods ; Humans ; Immunoglobulin A/metabolism ; Immunoglobulin G/metabolism ; Immunoglobulin M/metabolism ; Male ; Middle Aged ; Skin/metabolism/pathology ; Young Adult

Interleukin (IL)-33 is an important mediator of innate immunity. Behcet's disease (BD) is an autoinflammatory disorder characterized by hyperactivity of the innate immune response. We measured serum levels of IL-33 and its receptor soluble ST2 (sST2) in patients with BD to investigate their association with disease activity. Serum levels of both IL-33 and sST2 were higher in patients with BD compared with those in normal controls (IL-33: 594.48+/-175.04 pg/mL in BD and 224.23+/-56.64 pg/mL in normal controls [P=0.048], sST2: 99.01+/-15.92 pg/mL in BD and 23.56+/-3.25 pg/mL in normal controls [P<0.001]). IL-33 and sST2 expression in skin tissue, as shown by immunohistochemistry, was higher in patients with BD compared with that in the normal controls. Serum sST2 level correlated significantly with the BD currently active form (BDCAF), Iranian BD dynamic activity measure (IBDDAM), erythrocyte sedimentation rate and C-reactive protein. Multiple linear regression showed that serum sST2 was an independent factor associated with IBBDAM (regression coefficient, 0.374; P=0.004), and BDCAF (regression coefficient, 0.236; P=0.047). These results demonstrate that IL-33 and sST2 are highly expressed in patients with BD and that serum sST2 is an independent factor associated with IBDDAM and BDCAF, suggesting a potential role for sST2 as a surrogate marker of disease activity in patients with BD.
Adult ; Behcet Syndrome/blood/*pathology ; Blood Sedimentation ; C-Reactive Protein/analysis ; Female ; Humans ; Immunohistochemistry ; Interleukins/*blood/metabolism ; Male ; Middle Aged ; Receptors, Cell Surface/*blood/metabolism ; Severity of Illness Index ; Skin/metabolism/pathology

BACKGROUND: Thiopurine S-methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurines including azathioprine (AZA), 6-mercaptopurine, and 6-thioguanine. TPMT genotyping is widely used for screening of AZA-related toxicity during routine clinical practice in Korea. However, the data of TPMT genotypes and its AZA-related toxicity have not been studied in the field of dermatology. OBJECTIVE: The aim of this study was to evaluate the genetic basis of TPMT polymorphism in Korean dermatologic patients and subsequently to investigate the relationship between mutant TPMT and adverse responses to AZA treatment. METHODS: This study was retrospective, single-center study. One hundred forty-nine Korean dermatologic patients who underwent TPMT screening test were included. Each patient's medical records, the result of TPMT screening test, dose and treatment period of AZA, and side effects, were reviewed. Laboratory tests were assessed at each visit in order to monitor adverse drug reactions. Leukopenia grading was used in accordance with the common terminology criteria for adverse events (CTCAE) ver. 4.03. RESULTS: Behçet's disease was the leading disorder among the patients. The frequency of TPMT mutation was 4.0% (6/149) among the participants in this study. Four of the six patients with genetic alterations were treated with a low-dose AZA regimen, but no AZA-related adverse events were observed. CONCLUSION: Our results suggest that 1) TPMT polymorphisms in Korean dermatologic patients are similar to those previously reported in Asian patients with the most common mutant allele being TPMT*3C and 2) AZA can be used in the patients with these polymorphisms under a careful dosing regimen.
6-Mercaptopurine ; Alleles ; Asian Continental Ancestry Group ; Azathioprine ; Behcet Syndrome ; Dermatology ; Drug-Related Side Effects and Adverse Reactions ; Genotype ; Humans ; Korea ; Leukopenia ; Mass Screening ; Medical Records ; Metabolism ; Retrospective Studies ; Thioguanine

Recently, subpopulations of regulatory T (Treg) cells, resting Treg (rTreg) and activated Treg (aTreg), have been discovered. The authors investigated the relationship between the change of Treg, aTreg and rTreg and autoimmune diseases. Treg cells and those subpopulations were analyzed by using the human regulatory T cell staining kit and CD45RA surface marker for 42 rheumatoid arthritis (RA), 13 systemic lupus sclerosis (SLE), 7 Behcet's disease (BD), and 22 healthy controls. The proportion of Treg cells was significantly lower in RA (3.8% +/- 1.0%) (P < 0.001) and BD (3.3% +/- 0.5%) (P < 0.01) compared to healthy controls (5.0% +/- 1.3%). The proportion of aTreg cells was also significantly lower in RA (0.4% +/- 0.2%) (P = 0.008) and BD (0.3% +/- 0.1%) (P = 0.013) compared to healthy controls (0.6% +/- 0.3%). The rTreg cells showed no significant differences. The ratio of aTreg to rTreg was lower in RA patients (0.4% +/- 0.2%) than that in healthy controls (0.7% +/- 0.4%) (P = 0.002). This study suggests that the decrement of aTreg not rTreg cells contributes the decrement of total Treg cells in peripheral blood of RA and BD autoimmune diseases. Detailed analysis of Treg subpopulations would be more informative than total Treg cells in investigating mechanism of autoimmune disease.
Adult ; Aged ; Antigens, CD4/metabolism ; Antigens, CD45/metabolism ; Arthritis, Rheumatoid/*immunology/metabolism ; Behcet Syndrome/*immunology/metabolism ; Female ; Forkhead Transcription Factors/metabolism ; Humans ; Interleukin-2 Receptor alpha Subunit/metabolism ; Leukocyte Count ; Lupus Erythematosus, Systemic/*immunology/metabolism ; Male ; Middle Aged ; T-Lymphocytes, Regulatory/*cytology/immunology/metabolism

OBJECTIVE: Behcet's disease (BD) is an autoimmune disorder that causes most commonly mouth and genital ulcerations and erythema nodules of the skin and currently has limited options of therapeutic medicines. Metformin is recently reported to suppress immune reaction, and we hypothesized that metformin could be an option for treatment of BD. METHODS: Thirty patients with BD were enrolled in this perspective single-blinded, before-after study. We recorded the changes in the mucocutaneous activity index for BD (MAIBD), relapse frequency, C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) after metformin treatment to assess the changes in the disease activity. We also analyzed the changes in the protein and mRNA expression levels of Foxp3, interleukin-35 (IL-35), transforming growth factor-β (TGF-β), Ror-γt, IL-17, and tumor necrosis factor- (TNF-) in these patients using ELISA and qRT-PCR. RESULTS: Of the 30 patients enrolled, 26 completed the trial. After the treatment, favorable responses were achieved in 88.46% (23/26) of the patients, and partial remission was obtained in 11.54% (4/26) of them. During the treatment, 8 patients complained of gastrointestinal side effects, for which 4 chose to withdraw from the study in the first week. Our results showed that metformin treatment decreased MAIBD and relapse frequency in the patients, and significantly lowered the clinical inflammatory indexes including CRP and ESR. The results of ELISA and qRT-PCR revealed that metformin treatment obviously increased Foxp3 and TGF-β expressions at both the protein and mRNA levels and significantly decreased the levels of ROR-γt, IL-17 and TNF- as well as IL-35 level in these patients. CONCLUSIONS Metformin treatment relieves the clinical symptoms, reduces the inflammatory reaction indexes and regulates the Treg/Th17 axis in patients with BD, suggesting the potential of metformin as a candidate medicine for treatment of BD.
Behcet Syndrome ; drug therapy ; metabolism ; Controlled Before-After Studies ; Forkhead Transcription Factors ; metabolism ; Humans ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Interleukin-17 ; metabolism ; Interleukins ; metabolism ; Metformin ; adverse effects ; therapeutic use ; Neoplasm Recurrence, Local ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; metabolism ; RNA, Messenger ; metabolism ; Recurrence ; Single-Blind Method ; T-Lymphocytes, Regulatory ; cytology ; Th17 Cells ; cytology ; Transforming Growth Factor beta ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism