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Objectives: To evaluate the similarities between LBAL (adalimumab biosimilar candidate) and the adalimumab reference product (ADL) in terms of efficacy and safety, including immunogenicity, in patients with active rheumatoid arthritis despite methotrexate treatment., Methods: This phase III, multicentre, randomised, double-blind, parallel-group, 56-week study was conducted in Japan and Korea. During the first 24 weeks, patients subcutaneously received 40 mg of LBAL or ADL every two weeks (LBAL and ADL groups). During the subsequent 28 weeks, the LBAL group patients and half of the ADL group patients received LBAL (L-L and A-L arms). The remaining ADL group patients continued to receive ADL (A-A arm). The primary efficacy endpoint was the change from baseline in disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) at Week 24. American College of Rheumatology (ACR) response rates, adverse events (AEs), and anti-drug antibody (ADA) were also assessed., Results: In total, 383 patients were randomised. The least squares (LS) mean changes from baseline in DAS28-ESR at Week 24 were -2.45 and -2.53 in the LBAL (n=191) and ADL (n=190) groups, respectively. The 95% confidence interval (CI; -0.139, 0.304) of the difference (0.08) was within the pre-specified equivalence margin (-0.6, 0.6). Up to Week 52, the decreases in DAS28-ESR were maintained in all three arms. No notable differences in ACR20/50/70 were observed. The AE and ADA incidences were comparable between the arms., Conclusions: LBAL was equivalent in efficacy and comparable in safety, including immunogenicity, to ADL. Switching from ADL to LBAL did not impact on efficacy and safety.

Objectives: To evaluate the performance of the 2019 European League against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for systemic lupus erythematosus (SLE) in Asian patients., Methods: We conducted an electronic medical chart review of patients with SLE and defined rheumatic diseases. Classification criteria of the 1997 ACR, 2012 Systemic Lupus International Collaborating Clinics (SLICC), and 2019 EULAR/ACR were examined based on sensitivity, specificity, positive predictive value, negative predicted value, and accuracy using clinical diagnosis as the gold standard., Results: A total of 335 SLE patients and 337 non-SLE patients were analysed. Non-SLE patients included rheumatoid arthritis (RA) (n=92), anti-phospholipid syndrome (APS) (n=57), mixed connective tissue disease (n=52), systemic sclerosis (n=43), primary Sjögren's syndrome (SS) (n=39), undifferentiated connective tissue disease (n=28), RA with secondary SS (n=24), dermatomyositis (n=1), and spondyloarthropathy (n=1). The sensitivity was 97.6% (95% confidence interval (CI): 0.954-0.989) for the 2019 EULAR/ACR criteria, 98.5% (95% CI: 0.966-0.995) for the 2012 SLICC criteria and 95.5% (95% CI: 0.927-0.975) for the 1997 ACR criteria. The specificity was 91.4% (95% CI: 0.879-0.942) for the 2019 EULAR/ACR criteria, 92.6% (95% CI: 0.892-0.951) for the 2012 SLICC criteria 93.8% (95% CI: 0.906-0.961) for the 1997 ACR criteria., Conclusions: The 2019 EULAR/ACR criteria for SLE had comparable performance to the 2012 SLICC criteria regarding diagnostic sensitivity and specificity in Korean population of SLE and other rheumatic diseases. However, the new criteria could not reach higher specificity than the 2012 SLICC criteria.

Objectives: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we present data from the completed Phase 3 randomised controlled trial (RCT) ORAL Scan (NCT00847613), which evaluated the impact of tofacitinib on patient-reported outcomes (PROs) through 24 months in patients with active RA and inadequate responses to methotrexate (MTX-IR)., Methods: Patients were randomised 4:4:1:1 to receive tofacitinib 5 or 10 mg twice daily (BID), or placebo advanced to tofacitinib 5 or 10 mg, plus background MTX. Patients receiving placebo advanced to tofacitinib at month 3 (non-responders) or month 6 (remaining patients). Mean changes from baseline in PROs, assessed at months 1-24, included Health Assessment Questionnaire-Disability Index, Patient Global Assessment of disease activity (visual analogue scale [VAS]), Patient Assessment of Arthritis Pain (VAS), health-related quality of life (Short Form-36 version 2), Functional Assessment of Chronic Illness Therapy-Fatigue and Medical Outcomes Study-Sleep., Results: Overall, 539/797 (67.6%) patients completed 24 months' treatment. At month 3, tofacitinib-treated patients reported signi cant (p<0.05) mean changes from baseline versus placebo across all PROs, and significantly more patients reported improvements ≥ minimum clinically important differences versus placebo. Improvements in PROs with tofacitinib were sustained to month 24. Following advancement to tofacitinib, placebo-treated patients generally reported changes of similar magnitude to tofacitinib-treated patients., Conclusions: Patients with RA and MTX-IR receiving tofacitinib 5 or 10 mg BID plus MTX reported significant and clinically meaningful improvements in PROs versus placebo at month 3, which were sustained through 24 months.

Objectives: To perform unbiased analysis of fever patterns and to investigate their association with clinical manifestations and outcome of patients with adult-onset Still's disease (AOSD)., Methods: AOSD patients who were treated as in-patients from 2004 through 2015 were grouped according to 24-hour body temperature (BT) by hierarchical clustering using a Euclidean distance metric with complete linkage. The clinical and laboratory characteristics of the groups were then examined., Results: Hierarchical clustering partitioned 70 AOSD patients into three distinct groups. Group 1 (n=14) had the highest mean BT (38.1± 0.4°C) and the widest variation in BT (2.7±0.9°C). Group 2 (n=35) had a lower mean BT (37.4±0.3°C) and a smaller variation (2.1±0.7°C). Group 3 (n=21) had the lowest mean BT (36.7±0.3°C) and the smallest variation (1.5±0.6°C). Clinical features and extent of organ involvement did not differ significantly between groups. However, Group 1 had lower platelet counts and higher lactate dehydrogenase, ferritin levels, and prothrombin time than the other groups. In addition, Group 1 exhibited higher risk of having a macrophage activation syndrome (MAS) and tended to require more intense treatment with corticosteroids and immunosuppressant to achieve clinical remission as compared to other groups., Conclusions: Hierarchical clustering identified three distinct fever patterns in patients with AOSD. Higher BT was associated with wider variations in diurnal temperature, higher risk of developing MAS, more intense treatment, and longer time to clinical remission, suggesting that fever pattern is a prognostic factor for AOSD.

Objectives: To investigate the expressions of interferon (IFN)-λs and their receptor, IL28RA, in minor salivary glands (MSG) of pSS patients and their effects on the salivary gland cells., Methods: The expressions of IFN-λs and IL28RA were evaluated in MSG by immunohistochemistry in 15 patients with pSS and in 5 patients with non-SS sicca. Poly(I:C)-induced IL-28A and IL-29 expressions were determined in immortalized human salivary gland acinar (NS-SV-AC) and ductal (NS-SV-DC) cell lines. We assessed the effect of IFN-λs on the expressions of typical interferon-inducible genes, B-cell activating factor (BAFF) and CXCL10, and the synergistic effect of IL-29 and type I or II IFN on their expressions. The serum IL-29 levels were measured in 44 patients with pSS and 22 healthy controls., Results: IFN-λs expression was significantly higher in MSG from pSS than from non-SS sicca controls. Poly(I:C) treatment led to the induction of IL-28A and IL-29 in the salivary gland cell lines. In the NS-SV-DC cells, IFN-λ significantly increased the levels of BAFF and CXCL10 in a time and dose-dependent manner. Moreover, there was a synergistic effect between IL-29 and IFN-α in the induction of BAFF and CXCL10 expressions by prolonged STAT1 phosphorylation. However, the serum IL-29 levels were not significantly higher in pSS patients than in healthy controls., Conclusions: Our results suggest the possibility for IFN-λ to play a role by participating local inflammation in the salivary glands of pSS through direct and indirect regulations of the expressions of BAFF and CXCL10 in salivary gland epithelium.

Objectives: Behçet's disease (BD) is a chronic inflammatory disease of unknown etiology, characterised by recurrent oral and genital ulcers, skin lesions, uveitis, and arthritis. It is regarded as vasculitis and anti-endothelial cell antibodies (AECA) are found in patients with BD. One of the endothelial cell antibodies was reported to recognise alpha-enolase. This study aimed to investigate expression of alpha-enolase in the surface of peripheral blood cells and serum anti-alpha-enolase antibody (AEA), and their association with clinical manifestations or disease activity of BD., Methods: Cell surface alpha-enolase expression was examined from several cell types of peripheral blood, including lymphocytes, monocytes, and neutrophils using flow cytometry in patients with BD and healthy controls (HCs). IgG AEA levels were measured by enzyme-linked immunosorbent assay (ELISA) in sera from 110 patients with BD, and age/sex matched 110 HCs. Association of alpha-enolase or AEA with clinical manifestation was analysed., Results: The frequency of surface alpha-enolase-expressing cells was increased in BD in lymphocytes and monocytes. Serum AEA levels were in- creased in BD patients (median [IQR], 0.360 [0.268-0.482], p < 0.0001), particularly with mucocutaneous involvement (0.367 [0.273-0.490], p < 0.0001) compared to HCs (0.274 [0.231-0.357]). The levels of AEA were correlated with the number of oral ulcer, ESR, and CRP. There was no association between serum levels of AEA and other clinical manifestations., Conclusions: Serum AEA was increased in BD patients and correlated with oral ulcer, ESR and CRP.

Objectives: To investigate the efficacy and safety of low-dose etanercept treatment after clinical remission of ankylosing spondylitis (AS) in the real world., Methods: Data on 134 AS patients who were treated with etanercept for more than 12 months and achieved clinical remission (BASDAI<4 and CRP<0.5 mg/dL) were extracted from a large single centre registry. Drug survival and incidence of adverse events in 100 patients who reduced the dose during follow up (low-dose group) were compared with 34 patients who maintained the initial dose (standard-dose group). For minimisation of selection bias between the two groups, the same analyses were performed in a propensity score-matched population., Results: Both groups showed similar BASDAI score and CRP levels during the follow-up. Drug survivals between the two groups were also comparable up to 4 years (vs. standard-dose group, adjusted HR=0.472, 95% CI 0.155-1.435). The same analysis performed after propensity score-matching showed concordant result. The incidence of injection site reactions in the low-dose group was significantly lower, and the incidence of other adverse events showed no differences between the two groups. In the low-dose group, dose reduction after more than 24 weeks of standard-dose treatment was associated with longer drug survival (adjusted HR=0.261, 95% CI 0.084-0.809)., Conclusions: Low-dose etanercept treatment after achieving clinical remission can be an alternative treatment option in terms of its comparable long-term efficacy and favourable safety in AS. More than 24 weeks of standard-dose treatment before dose reduction may be beneficial for longer drug survival in this strategy.

Objectives: Clinical features of primary Sjögren's syndrome (pSS) overlap with those of fibromyalgia (FM). This cross-sectional study was conducted to investigate the prevalence of FM in pSS patients and to compare the clinical features of pSS patients with FM to those without FM., Methods: One hundred pSS patients were consecutively assessed to identify the presence of FM according to the American College of Rheumatology (ACR) 2010 criteria. Clinical and laboratory data were collected from all patients. Additional assessments included EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). The severity of depression was measured by Hamilton depression rating scale 17-items (HAM-D scale)., Results: The prevalence of FM was 31.0% (31/100) in pSS. Widespread pain index and symptom severity scale were significantly correlated with ESSPRI (r=0.6542 and r=0.7173, both p<0.0001) and HAM-D scale (r=0.6734 and r=0.6471, both p<0.0001) in pSS. In multivariate analysis, ESSPRI and HAM-D scale were independently associated with increase of tender point count and symptom severity scale. ESSPRI was significantly higher in pSS patients with FM compared to those without FM (p<0.0001). The prevalence of FM in pSS patients with moderate-to-severe depression was significantly higher than those with mild depression or without depression (odds ratio= 10.62, p=0.0009). Serum 25-hydroxy vitamin D3 levels in pSS patients with FM were significantly (p=0.0072) decreased compared to those without FM., Conclusions: Our study showed that FM was prevalent in pSS. FM was associated with higher ESSPRI and more severe depression.

Objectives: High-resolution MR angiography (HR-MRA) demonstrates blood flow in the digital arteries, which correlates with the severity of Raynaud's phenomenon (RP). This study investigates whether baseline HR-MRA of the hand can predict the treatment response to udenafil, a new PDE5-inhibitor, in patients with secondary RP., Methods: Baseline MRA and Doppler ultrasound were obtained in 12 patients with secondary RP. The patients were treated with udenafil 100 mg/day for 4 weeks and changes in blood flow were measured. Blood flow on MRA was scored on a 4-point scale: 0, no visible flow; 1, visible flow to the proximal phalanx; 2, to the middle phalanx; and 3, to the distal phalanx. Peak systolic velocity (PSV) was measured to determine blood flow. Paired t-test and ANOVA were used to determine the treatment response of the different MRA scores., Results: On baseline MRA, 53.3% of digital arteries had an MRA score of 0, 25.8% MRA score of 1, 9.2% MRA score of 2, and 11.6% MRA score of 3. Overall, 4-week udenafil treatment improved digital flow (p<0.05) in all MRA scores. Digital arteries with MRA score 2 showed the best response with improvement in PSV by 14.5 mm/sec (p<0.01), whereas improvement in arteries of MRA scores 1 and 3 were not better than an MRA score of 0 (all, p>0.05)., Conclusions: Digital arteries with moderate blood flow observed on MRA respond best to treatment with udenalfil. Therefore, baseline MRA may help predict treatment response in patients with secondary RP.

Objectives: Previous genome-wide association studies have demonstrated an association between the IL-10 region and Behçet's disease (BD) in Turkish and Japanese populations. Our aim was to fully examine the relationship between IL-10 and BD, the associations between BD and single nucleotide polymorphisms (SNPs) in IL-10-mediated signalling pathways (JAK1, TYK2, and STAT3) were examined in Korean patients with BD., Methods: DNA samples were obtained from 223 patients who met the international study group criteria for BD and from 222 age- and sex-matched healthy controls. Twenty-four tag SNPs in JAK1, STAT3, and TYK2 were selected for genotyping based on the Japanese panel of international HapMap data with a minor allele frequency >5% and r2 >0.8., Results: The allele-based analysis showed that the T allele of rs310245 in JAK1 was associated with BD (odds ratio [95% confidence interval] = 1.34 [1.03-1.76], p=0.031), which lost statistical significance after permutation-based correction for multiple testing. In the genotype-based analysis, the JAK1 rs310245 TT homozygote (1.79 [1.14-2.82], p=0.012) and the STAT3 rs2293152 GG homozygote (2.01 [1.16-3.47], p=0.011) showed associations with BD. However, these associations did not achieve significance after correction for multiple testing. We did not observe any genetic interaction between the JAK1 rs310245 TT homozygote and the STAT3 rs2293152 GG homozygote. In the haplotype analysis, GT haplotype at rs17127024 and rs310245 (1.34 [1.03-1.74], p=0.032), and the AA haplotype at rs2256298 and rs3818753 (1.41 [1.03-1.92], p=0.034) in JAK1 were associated with BD, but lost statistical significance after correction for multiple testing., Conclusions: There was no significant association between BD and SNPs in IL-10-mediated intracellular signalling in Korean patients.

Objectives: The accurate assessment of proteinuria is critical for the management of lupus nephritis. Measuring the protein to creatinine (P/C) ratio in random spot urine (RSU) samples has been introduced as an alternative to the 24-hour (24h) urine collection method. However, it remains unclear as to whether the RSU P/C ratio is reliable for assessing lupus nephritis (LN) in routine clinical practice., Methods: In total, 275 pairs of 24h urine and RSU samples from 102 patients with biopsy-proven LN were analysed. The correlation and concordance between the P/C ratios in the two sample types were assessed by Pearson or Spearman correlation and intra-class correlation coefficient (ICC) using mixed models for repeated measurements, respectively., Results: The mean 24h urine P/C ratio was 3.2 ± 4.9. Overall, RSU P/C ratio correlated strongly with the 24h urine P/C ratio (r=0.944, p<0.001) with an excellent agreement (ICC=0.949, 95% confidence interval [CI]: 0.69-1.00). Subgroup analyses revealed that the correlation remained high in class II, III, IV, and V LN (rho=0.868, p<0.001; rho=0.649, p=0.007; r=0.945, p<0.001; and rho=0.900, p=0.001, respectively). The correlation between the 24h urine and RSU P/C ratio in the range of 0.5 to 3 was good (r=0.720, p<0.001) with ICC of 0.659 (95%CI 0.554-0.812). RSU P/C ratio ≥0.5 could predict 24h PCR ≥0.5 with 91.7% sensitivity and 70.2% specificity, whereas RSU P/C ratio ≥1.0 increased specificity up to 94.7%., Conclusions: The RSU P/C ratio is an excellent alternative to the 24 hour P/C ratio for assessing the presence of clinically significant proteinuria in LN. RSU P/C ratio >1.0 may prompt directly to a renal biopsy, whereas RSU P/C ratio between 0.5-1.0 should be followed by a confirmatory 24h urine collection.

Objectives: To compare salivary cytokine profiles in patients with primary Sjögren's syndrome (pSS), non-SS sicca controls, and non-sicca controls, and to investigate whether cytokine levels are correlated with clinical parameters of pSS patients., Methods: Un-stimulated whole saliva samples were obtained from pSS patients (n=30) classified according to the criteria of the American European Consensus Group. Age- and gender-matched non-SS sicca patients (n=30) and non-sicca subjects (n=25) served as controls. Salivary IFN-γ, TNF-α, IL-1, IL-4, IL-6, IL-10, IL-12p40, and IL-17 levels were measured using a multiplex Luminex® bead-based assay., Results: pSS patients and non-SS sicca controls had significantly lower salivary flow rates (SFRs) than non-sicca controls, and pSS patients showed a more profound decrease than non-SS sicca controls. In addition, pSS patients and non-SS sicca controls had higher levels of IFN-γ, TNF-α, IL-1, IL-4, IL-10, IL-12p40, and IL-17 in their saliva than non-sicca controls. Salivary TNF-α levels were higher in pSS patients than in non-SS sicca controls. Th-1/Th-2 ratios, represented by INF-γ/IL-4 and TNF-α /IL-4 ratios, were significantly higher in pSS patients than in non-SS sicca controls. SFR was found to be correlated with INF-γ/IL-4 ratio (r=0.411 p=0.024), and focus score to be correlated with TNF-α/IL-4 ratio (r=0.581, p=0.023) in pSS patients., Conclusions: Th-1, Th-2, and Th17 cytokine levels were found to be elevated in the saliva of pSS patients compared with non-sicca controls. However, considerable overlap was observed between the salivary cytokine levels of pSS patients and of non-SS sicca controls. The features that most differentiated pSS and non-SS sicca were higher TNF-α levels and Th-1/Th-2 ratios. Th-1/Th-2 ratio was also found to be correlated with the clinical parameters of pSS.

Objectives: Behçet's disease (BD) may be triggered by infectious agents in genetically susceptible persons. Human β-defensin 2 is an inducible antimicrobial peptide, the level of which can be influenced by copy number (CN) of the DEFB4. We investigated the relationship between copy number variation (CNV) of DEFB4 and BD., Methods: One hundred and ninety-seven patients with BD and 197 healthy controls were enrolled. After measuring CN of DEFB4 with a paralogue ratio test, the CNV was compared between patients and controls. CNV was also analysed in comparison with the clinical manifestations of BD., Results: The CN of DEFB4 was unimodally distributed among the study subjects with mean CN of 4.57 and standard deviation of 1.28. BD samples had numerically lower CN than controls, but the difference was not statistically significant (4.49 ± 1.21 vs. 4.65 ± 1.36, p=0.245). Regarding the relationship between CN of DEFB4 and clinical manifestations, there was no difference of CNV depending on the clinical manifestations., Conclusions: We found no significant difference in CNV of DEFB4 between patients with BD and controls. Our results suggest that CNV of DEFB4 may not contribute to the pathogenesis of BD.

Objectives: Behçet's disease (BD) is a helper T cell-mediated autoimmune disease characterised by recurrent orogenital ulcers, uveitis and skin lesions. The helper T cells are divided into Th1, Th2 and Th17 cells according to the pattern of cytokine secretion. Th1 and Th17 cells can contribute to the development of the disease with their respective proinflammatory cytokines, IFN-γ and IL-17. In this study, we investigated the relative role of Th17, Th1 and Th2 cells in BD., Methods: Peripheral blood mononuclear cells were isolated from 30 patients with BD, for whom the detailed clinical manifestations and medication history were investigated and recorded. Surface markers and intracellular levels of IL-17, IFN-γ and IL-4 in isolated CD4+ T cells were measured using flow-cytometry from these patients and from two control groups, 34 rheumatoid arthritis patients and 24 healthy blood donors to analyse the relationship of Th1, Th17 and Th2 cells in BD., Results: The ratio of Th17/Th1 cells was significantly increased in BD compared to healthy controls (0.16±0.09 vs. 0.10±0.04, p=0.012), while there was no difference in the ratios of Th1/Th2 or Th17/Th2 cells. Th17/Th1 ratio was elevated in BD patients with uveitis or folliculitis compared to those without it (0.21±0.10 vs. 0.13±0.06, p=0.045 for uveitis; 0.18±0.10 vs. 0.12±0.05, p=0.036 for folliculitis)., Conclusions: Our results confirm that TH17 cells are instrumental in Behçet's uveitis and folliculitis. Furthermore, our findings suggest that the role of Th17 cells should be interpreted in the context of their ratio to Th1 cells.

Objective: To investigate the role of sTREM-1 and PTX3 as markers of infection in febrile patients with SLE., Methods: In febrile (body temperature > or =38 degrees C) patients with SLE, blood samples of day 0, 1, 2, and 14 after presentation were drawn and relevant clinical data were collected. The patients were allocated to an infection group (n=19) or disease flare group (n=14). Serum levels of sTREM-1 and PTX3 were measured by ELISA using the serum samples of SLE patients and age- and sex-matched healthy controls (n=31)., Results: A total of 33 febrile episodes occurred in 32 SLE patients (19 infections, 14 flares) were studied. sTREM-1 levels on day 0 were significantly higher in the infection group than in the flare group (109.9 pg/ml (median) vs. 48.0 pg/ml, p=0.002), but PTX3 levels were similar in these two groups. The difference of sTREM-1 levels between infection group and flare group was persistent on day 1 and 2 (day 1, p=0.007; day 2, p=0.034). The highest diagnostic value (sensitivity=1.0, specificity=0.664) of sTREM-1 was obtained at the threshold value of 53.2 pg/mL., Conclusion: Serum sTREM-1 levels were significantly higher in the infection group than in the flare group of febrile SLE patients. Our findings suggest that serum sTREM-1 levels could be used to determine whether SLE patients have contracted an infection.

Objective: Ankylosing spondylitis (AS) is an inflammatory arthritis involving the axial skeleton. Decreased bone mineral density has also been reported in AS patients. This study sought to determine whether osteoclastogenesis and osteoclast activity are increased in AS., Methods: Twenty patients with AS were evaluated using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and other clinical parameters. Mononuclear cells were separated out from peripheral blood samples taken from AS patients and normal healthy controls and cultured with monocyte colony stimulating factor and receptor activator of the nuclear factor kappa B ligand (RANKL). Multi-nucleated, tartrate-resistant acid phosphatase stain-positive osteoclasts were counted after 9 days, and the areas of calcium absorption on calcium-coated plates were determined., Results: Osteoclastogenesis was significantly greater in AS patients than in normal controls (number of osteoclasts/1106 mononuclear cells, median, 518.0 vs. 362.5, p=0.036). No differences were observed between AS patients and controls in terms of calcium absorption areas or the serum concentrations of tumor necrosis factor and RANKL. Osteoclastogenesis was greater in AS patients with sacroiliac joint ankylosis than in those without. Osteoclastogenesis and the calcium absorption area were not found to be correlated with BASDAI nor with other clinical parameters including age, erythrocyte sedimentation rate, and C-reactive protein levels., Conclusion: Osteoclastogenesis is elevated in AS patients, especially in those with sacroiliac joint ankylosis. Increased osteoclastogenesis may be related to osteopenia in AS patients.

Objective: Behçet's disease (BD) is an autoimmune disease with an unknown etiology and mannose-binding lectin (MBL) is a pattern recognition receptor in the innate immune system, which is associated with some autoimmune diseases. We investigated MBL2 gene polymorphisms and serum MBL levels in BD patients and controls., Methods: MBL2 gene polymorphisms in exon 1 (MBL2 54 Gly/Asp, (A/B)), promoter (MBL2 H/L (G-550C), MBL2 Y/X (G-221C)), and 5' UTR region (MBL2 P/Q (C+4T)) were investigated using polymerase chain reaction and restriction fragment length polymorphism in 119 BD patients and 252 healthy controls. Serum MBL levels were measured by enzyme linked immunosorbent assay in 49 BD patients and 102 sex-/genotype-matched controls., Results: No significant difference was found between BD patients and controls in terms of MBL2 polymorphisms and MBL serum levels. However, the presence of genital ulcer and neurologic involvement were found to be associated with MBL2 54 allele A (OR=2.415, OR=6.632, respectively). Eye involvement was found to be related to the presence of the MBL2 54 AA or AB genotypes (OR=12.46), MBL2-G-550C allele H (OR=1.829). High serum MBL level (> or =500 ng/ml) was associated with skin lesions (p=0.002)., Conclusion: The frequencies of the four MBL2 genetic polymorphisms examined were not different in BD patients and healthy controls. However, the presence of genital ulcer, eye involvement, and neuro-Behcet's disease were found to be associated with MBL2 polymorphisms that are associated with the production of high levels of MBL or functional MBL.

Objective: To determine the serum levels of galectin-3 (Gal-3) and galectin-3 binding protein (G3BP) and to evaluate the associations between clinical features and these levels in patients with Behçet's disease (BD)., Methods: Fifty patients with BD (mean age 40.6 +/- SEM 1.4 years; 21 males, 29 females; 26 active and 24 inactive patients), 20 patients with rheumatoid arthritis (RA), and 20 patients with systemic lupus erythematosus (SLE) were enrolled. Clinical features of BD patients including BD activity and severity over the previous 4 weeks were reviewed and serum levels of Gal-3 and G3BP were determined using enzyme-linked immunosorbent assays (ELISA)., Results: Serum Gal-3 levels were significantly higher in total BD patients than in healthy controls (mean +/- SEM, 10.68 +/- 0.93 versus 7.59 +/- 0.48 ng/mL; p = 0.0042 by Student's t-test), and active BD patients had significantly higher levels of serum Gal-3 than inactive patients and controls (13.08 +/- 1.53 in active BD, 8.08 +/- 0.71 ng/mL in inactive BD; p = 0.000039 by one way ANOVA). Although mean G3BP serum levels were not different in total BD patients and controls, active BD patients (6806.63 +/- 468.58 ng/mL) had higher G3BP levels than controls (5421.05 +/- 286.02 ng/mL; p = 0.031 by one way ANOVA). Additionally, serum Gal-3 significantly increased in patients with RA (p = 0.019 by t-test) and SLE (p = 0.00069) and G3BP increased in patients with SLE (p = 0.000012), compared to those in healthy controls. When we analyzed for associations with clinical features over the previous 4 weeks, Gal-3 was associated with orogenital ulcers (p = 0.036 by t-test) and time elapsed from symptom onset (p = 0.032, Pearson's coefficient = 0.314). Serum concentrations of Gal-3 (p = 0.013) and G3BP (p = 0.032) were positively correlated with the BD severity score for the previous 4 weeks. Gal-3 levels were significantly correlated with TNF-alpha (p = 0.048, Pearson's coefficient = 0.281) and G3BP levels were correlated with levels of C-reactive protein (p = 0.021, Pearson's coefficient = 0.329) in total BD patients. In multivariate analysis of all cytokines levels, only Gal-3 was significantly related to BD activity or severity for the previous 4 weeks., Conclusion: These results suggest that serum levels of Gal-3 and G3BP are increased in active BD patients and Gal-3 can be a new biomarker indicating disease activity in BD although their increments are not disease-specific.

Objective: The rheumatoid synovium is a hypoxic environment, and hypoxia has been implicated as a factor in the pathogenesis of rheumatoid arthritis (RA). The purpose of this study was to investigate the effect of hypoxia on the expression of matrix metalloproteinase (MMP)-1, -3 and tissue inhibitor of metalloproteinase (TIMP)-1 in rheumatoid synovial fibroblasts., Methods: Synovial fibroblasts obtained from RA patients were cultured for 48 h under normoxic or hypoxic conditions. Assays included western blot analysis and enzyme-linked immunosorbent assay (ELISA) for MMP-1, -3 and TIMP-1, and northern blot analysis to measure TIMP-1 mRNA levels., Results: Compared with normoxic culture, hypoxia increased MMP-1 and MMP-3 expression in rheumatoid synovial fibroblasts. Hypoxia decreased TIMP-1 expression in rheumatoid synovial fibroblasts, as measured by both protein and mRNA levels., Conclusion: These results suggest that microenvironmental conditions, such as hypoxia, may directly contribute to joint destruction in RA by increasing the ratio of MMP-1, -3 to TIMP-1 production in synovial fibroblasts.

Objective: To evaluate the blood concentration of type III procollagen N-terminal propeptide (PIIINP), soluble interleukin-2 receptor (sIL-2R), and von Willebrand factor (vWF) in systemic sclerosis (SSc) patients., Methods: PIIINP, sIL-2R, and vWF were measured in the sera and plasma of 29 SSc patients and 29 sex- and age-matched healthy controls. Serum PIIINP was determined by radioimmunoassay. Both serum sIL-2R and plasma vWF were measured by enzyme-linked immunosorbent assay (ELISA). Associations between concentrations and clinical and laboratory features were evaluated., Results: Serum levels of PIIINP and sIL-2R were significantly higher in the SSc group than in the control group (p < 0.01 for both). No differences in serum PIIINP and sIL-2R levels were found between the limited and diffuse cutaneous subsets. However, PIIINP concentrations were significantly higher in anti-Scl-70 positive SSc patients compared with those of anti-Scl-70 negative patients (p = 0.01). Serum PIIINP levels were significantly higher in SSc patients with restrictive pulmonary function (FVC < 80%) than in patients with normal pulmonary function (p < 0.05). The correlation between PIIINP levels and FVC (p < 0.05) was negative, but the correlation between PIIINP levels and modified Rodnan skin scores (p < 0.05) was positive. sIL-2R levels were not correlated with skin and pulmonary involvement of SSc. There was no difference in vWF levels between those of the SSc patients and those of the control groups., Conclusion: These results suggest that serum PIIINP serves as a biologic marker for the extent of skin and pulmonary involvement in systemic sclerosis. Increased serum levels of sIL-2R in SSc patients support a role for T lymphocyte activation in the pathogenesis of systemic sclerosis.

Objective: To investigate the incidence and risk factors of Mycobacterium tuberculosis infection in longterm corticosteroid treated rheumatic disease patients., Methods: We assessed retrospectively the incidence of active tuberculosis and its risk factors in 269 rheumatic disease patients treated with moderate to high doses of corticosteroid for an evaluation period representing 1,035 corticosteroid years of therapy., Results: The mean daily dose of steroid was 18.7 mg prednisolone and the mean daily dose during the first year of treatment was 20.4 mg prednisolone. 21 of these patients developed active tuberculosis resulting in an incidence rate of 20/1,000 patient-years. Cumulative and mean daily steroid doses during the follow-up period and during the first year of treatment, and a history of steroid pulse therapy were significantly correlated with the development of tuberculosis. A past history of tuberculosis, initial chest P-A abnormality, the starting dose of steroid, a history of more than 30 mg/day of prednisolone for more than one month, and a history of cytotoxic therapy were not related to the development of tuberculosis., Conclusion: The incidence of active tuberculosis is increased in rheumatic patients on moderate-to-high dose steroid treatment. Its risk factors are the cumulative and mean daily steroid doses during the follow-up period and during the first year of steroid treatment, and a history of steroid pulse therapy.