Sialic-Acid-Related Enzymes of B Cells and Monocytes as Novel Markers to Discriminate Improvement Categories and to Fulfill Two Remission Definitions in Rheumatoid Arthritis.

The enzymes α-2,6-sialyltransferase 1 (ST6Gal1), neuraminidase 1 (Neu1), α-2,3-sialyltransferase 1 (ST3Gal1), and neuraminidase 3 (Neu3) are known to affect immune cell function. However, it is not known whether the levels of these enzymes relate to remission definitions or differentiate American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) responses in patients with rheumatoid arthritis (RA). We measured the ST6Gal1, Neu1, ST3Gal1, and Neu3 levels of B cells and monocytes in RA patients and correlated the cells' enzyme levels/ratios with the improvement in the ACR, EULAR and SDAI responses and with the two remission definitions. The difference in the B-cell Neu1 levels differed between the ACR 70% improvement and non-improvement groups (p = 0.043), between the EULAR good major response (improvement) and non-good response groups (p = 0.014), and also between the SDAI 50% or 70% improvement and non-improvement groups (p = 0.001 and 0.018, respectively). The same held true when the RA patients were classified by positive rheumatoid factor or the use of biologics. The B-cell Neu1 levels significantly indicated 2005 modified American Rheumatism Association and 2011 ACR/EULAR remission definitions (area under the curve (AUC) = 0.674 with p = 0.001, and AUC = 0.682 with p < 0.001, respectively) in contrast to the CRP and ESR (all AUCs < 0.420). We suggest that B-cell Neu1 is superior for discriminating ACR, EULAR, and SDAI improvement and is good for predicting two kinds of remission definitions.

A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis.

While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger's hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10-7-7.31 × 10-6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10-7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10-6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D' = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.

α-2,6-sialic acid/IgG anti-dsDNA ratios correlate with human lupus disease activity and possible mechanisms: A pilot study.

OBJECTIVE: To study the association of α2,6-sialic acid (SIA) content in serum IgG anti-dsDNA with human systemic lupus erythematosus disease activity index (SLEDAI) and the effect of sialylated and desialylated (deSIA) IgG anti-dsDNA on lupus B cells. METHODS: Blood from lupus patients was collected to determine the ratio of SIA in isolated IgG anti-dsDNA over serum IgG anti-dsDNA (SIA/IgG anti-dsDNA) ratios, which were plotted against SLEDAI using a receiver-operating-characteristics curve. Lupus B cells were cultured in vitro with chimeric sialylated IgG anti-dsDNA and its deSIA form. Culture supernatants were assayed for anti-inflammatory IL-10 and SIA/IgG anti-dsDNA ratios, which were compared among different pre-treatment groups using t-tests. RESULTS: The area-under-the-curve (AUC) for anti-dsDNA levels against SLEDAI was 0.791 positively (95% confidence interval [C.I.]: 0.699-0.884) and SIA/IgG anti-dsDNA ratios against SLEDAI yielded an AUC of 0.705 inversely (95% C.I: 0.601-0.809): not significantly different. SIA/IgG anti-dsDNA ratios discriminated significantly between patients without and patients with proteinuria (p = .046). SIA/IgG anti-dsDNA ratios correlated significantly and positively with serum C3c and C4 levels. Pre-treatment with IgG anti-dsDNA and its immune complexes (dsDNA/IgG anti-dsDNA IC) induced higher IL-10 from lupus B cells than medium pre-treatment (most p < .01 from day 2 to day 5 culture). DeSIA IgG anti-dsDNA IC induced lower IL-10 (p < .05) and lower SIA/IgG anti-dsDNA ratios (p < .001) from lupus B cells than medium and dsDNA pre-treatment. CONCLUSION: α2,6-SIA/IgG anti-dsDNA ratios inversely forecasted SLEDAI scores. Possible mechanisms may be due to the different effects of sialylated and deSIA IgG anti-dsDNA on lupus B cells in terms of IL-10 secretion and SIA/IgG anti-dsDNA ratios.

De-sialylated and sialylated IgG anti-dsDNA antibodies respectively worsen and mitigate experimental mouse lupus proteinuria and possible mechanisms.

BACKGROUND: The role of sialylated and de-sialylated (de-SIA) IgG anti-dsDNA antibodies in experimental mouse lupus remains unclear. AIM OF THE STUDY: To examine how sialylated and de-SIA IgG anti-dsDNA antibodies affect lupus mouse proteinuria and possible mechanisms. METHODS: Blood was serially obtained from pristane-induced female BALB/c lupus mice to assess correlations between alpha-2,6-sialic cid (SIA) ratios of serum IgG anti-dsDNA and proteinuria. Kidney C3 staining was correlated with blood IgG anti-dsDNA. Sialylated IgG anti-dsDNA with its de-SIA form was administered to determine the effect on lupus proteinuria and in vitro consequences. RESULTS: We observed that the SIA contents of IgG anti-dsDNA were lower in Week 16/1+ (Week 16 with 1 + proteinuria) and W24/2 + mice than those in W16 (no proteinuria) and W24/1 + mice, respectively (P < 0.005 for both). C3 staining densities in the kidney correlated inversely with the α-2,6-SIA content of plasma IgG anti-dsDNA (r = -0.660). Highly sialylated A52L1 IgG anti-dsDNA injection mitigated lupus proteinuria significantly from PBS injection; however, its de-SIA form worsened proteinuria (aggravation of proteinuria: the latter vs. the former [sialylated A52L1 IgG anti-dsDNA] with an infinite odds ratio). Highly sialylated A52L1 IgG anti-dsDNA resulted in higher interleukin (IL)-10/IL-12 ratios, higher transforming growth factor-ß1 levels, and lower tumor necrosis factor-α levels in sera than its de-SIA from. CONCLUSION: We concluded that a low SIA/serum IgG anti-dsDNA ratio indicated a high severity of nephritis in pristane-induced lupus mice. Highly sialylated IgG anti-dsDNA, in contrast to the de-SIA form, alleviated the severity of lupus proteinuria.

Reverse expression of α2,6-sialic acid ratios on IgG, IgM, and IgG/IgM autoantibodies correlates with mouse arthritis and rheumatoid arthritis disease activity.

BACKGROUND: Sialic acids (SIAs), for example, α2,6-SIAs, can link to conserved N-glycans of immunoglobulin G (IgG). In this study, we investigated the correlation between α2,6-SIA on IgG and IgM and the disease activity of arthritis and rheumatoid arthritis (RA) in mice. METHODS: We measured α2,6-SIA levels in IgGs and IgMs in collagen-induced arthritis (CIA). Additionally, α2,6-SIA levels in rheumatoid factors (RFs) and anti-cyclic citrullinated peptide (anti-CCP) antibodies in RA patients were measured. Correlations between α2,6-SIA on Igs and CIA were analyzed and also in RA patients by utilizing the disease activity score 28 (DAS28). The ability to differentiate RA progression by Ig and autoantibody α2,6-SIA levels was examined. RESULTS: In CIA mice, plasma IgG-α2,6-SIA/IgG ratios decreased, whereas plasma IgM-α2,6-SIA/IgM ratios increased. Moreover, arthritis was not observed in collagen-injected mice with decreased IgG-α2,6-SIA/IgG ratios and without increased IgM-α2,6-SIA/IgM ratios. Isolated IgG-α2,6-SIA/IgG ratios displayed a significant inverse correlation with DAS28 scores (r = -0.383, p = 0.037). In contrast, isolated IgM-α2,6-SIA/IgM ratios correlated positively with DAS28 (r = 0.351, p = 0.009). Isolated IgG-anti-CCP-α2,6-SIA/plasma IgG-anti-CCP ratios were differentiated into either the remission (higher ratios) or the nonremission (lower ratios) category (p = 0.061), which is similar to the pattern for C-reactive protein (CRP) (p = 0.041) but different from that for the erythrocyte sedimentation rate (ESR) (p = 0.421). Using multiple linear regression analysis, plasma IgMRF-α2,6-SIA/IgMRF ratios displayed a correlation with DAS28 (p = 0.006), which was also observed in the ESR (p = 0.005), but was different from that for CRP (p = 0.222). CONCLUSION: Concurrent reverse expression of α2,6-SIA ratios on IgM and IgG correlated with the occurrence of CIA and RA disease activity. Thus, α2,6-SIA ratios on IgG-anti-CCP antibodies and IgMRF are potential markers for evaluating RA disease activities.

A new laboratory surrogate (Monocyte Chemotactic Protein-1) for Disease Activity Score28: a favourable indicator for remission in rheumatoid arthritis.

This prospective one-year follow-up study was conducted from 835 visits in 178 rheumatoid arthritis (RA) patients. Tender-/swollen-joint count, Health Assessment Questionnaire Disability Index (HAQ-DI), Disease Activity Score 28-ESR (DAS28-ESR), DAS28-CRP, Simplified Disease Activity Index (SDAI) and DAS28-monocyte chemotactic protein-1 (DAS28-MCP-1) scores were obtained every 3 months. Radiographs of hands and feet were acquired at baseline and one year. We evaluated the correlation and accuracy of activity scores in predicting remission, HAQ-DI changes and radiographic changes. DAS28-MCP-1 correlated strongly with DAS28-ESR, DAS28-CRP and SDAI scores (0.830, 0.899 and 0.931, respectively, with all P < 0.001). Score changes of DAS28-MCP-1 were comparable to those of DAS28-ESR, DAS28-CRP and SDAI in predicting changes in HAQ-DI and bone erosion. DAS28-MCP-1 (<2.2) was better than DAS28-ESR (<2.6) in indicating modified American Rheumatism Association remission and 2011 American College of Rheumatology/European League Against Rheumatism remission (75.61% vs. 36.99% and 81.71% vs. 49.13%, respectively) with odds ratios of 5.28 and 4.62 (both P < 0.001), respectively. We compared DAS28-MCP-1 with SDAI (≦3.3) in indicating remission with odds ratios of 2.63 (P = 0.002) and 0.98, respectively (and DAS28-MCP-1 with DAS28-CRP < 2.5: 1.33 and 0.92). Therefore, DAS28-MCP-1 is useful as an alternative in assessing RA activity.

α-2,3-Sialyltransferase 1 and neuraminidase-3 from monocytes in patients with rheumatoid arthritis correlate with disease activity measures: A pilot study.

BACKGROUND: We decided to study the association of monocyte α-2,3-sialyltransferase 1 (ST3Gal-1), neuraminidase-3 (Neu3), α-2,6-sialyltransferase 1 (ST6Gal-1), and neuraminidase-1 (Neu1) levels with disease activity score 28 (DAS28) in human rheumatoid arthritis (RA), considering that mouse monocytes' sialic acid (SIA) levels relate to their phagocytosis and IgG binding ability. METHODS: ST3Gal-1, Neu3, ST6Gal-1, Neu1, α-2,3-SIA, and α-2,6-SIA levels on RA peripheral blood monocytes, T cells, and polymorphonuclear cells were determined by using fluorochrome-conjugated anti-cell-specific marker antibodies and fluorochrome-conjugated anti-enzyme antibodies. Simple correlation and linear regression were used to correlate enzyme levels with DAS28. RESULTS: RA monocyte ST3Gal-1 and Neu3 levels correlated with DAS28 in patients having DAS28 >5.1 (r = 0.469, p = 0.002; r = 0.410, p = 0.006, respectively). When multivariable analysis was performed for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and SIA-related enzyme levels in different cell types as independent variables with DAS28 as a dependent variable, monocyte ST3Gal-1 levels correlated with DAS28 (p = 0.009) but not ESR and CRP in patients having DAS28 >5.1 (both p ≥ 0.292). RA monocyte ST3Gal-1 levels correlated with DAS28 (p = 0.010) and with ESR (p < 0.001) at month 0 when applied to all RA patients including both remission and nonremission groups in multivariable analysis. The latter findings persisted longitudinally at month 3. CONCLUSION: Monocyte ST3Gal-1 and Neu3 levels correlated longitudinally with DAS28 by two different methods suggest that monocyte ST3Gal-1 and Neu3 levels may be used as biomarkers to monitor RA disease activity.

Sialyltransferase and Neuraminidase Levels/Ratios and Sialic Acid Levels in Peripheral Blood B Cells Correlate with Measures of Disease Activity in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis: A Pilot Study.

OBJECTIVE: We attempted to determine whether the level of enzymes sialyltransferase (ST) and neuraminidase (Neu) and sialic acid (SIA) in patients with systemic lupus erythematosus (SLE) correlates with the SLE Disease Activity Index (SLEDAI) and in patients with rheumatoid arthritis (RA) correlates with the Disease Activity Score28 (DAS28). METHODS: We examined cell-surface levels of ST6Gal-1, Neu1, ST3Gal-1, Neu3, α-2,6-SIA, and α-2,3-SIA by using fluorescent anti-enzyme antibodies, fluorescent-conjugated Sambucus nigra lectin, and fluorescent-conjugated Maackia amurensis lectin on blood cells in SLE and RA patients and assessed correlations of these levels with SLEDAI and with DAS28. Areas under the curve (AUC) were calculated for different variables against SLEDAI. RESULTS: The B-cell ST3Gal-1/Neu3 ratio positively correlated with SLEDAI scores (ρ = 0.409 and P = 0.002, statistically significant after Bonferroni' correction for multiple analyses.). It was supported by the inverse correlation of B-cell Neu3 levels with SLEDAI scores (ρ = -0.264, P = 0.048). The B-cell ST3Gal-1/Neu3 ratio against SLEDAI yielded an AUC of 0.689, which was comparable to that of anti-dsDNA levels at 0.635. In contrast, both ST3Gal-1 and Neu3 levels of RA B cells (r = 0.376, P = 0.013; r = 0.425, P = 0.005, respectively) correlated positively with high disease-activity DAS28 scores. CONCLUSION: B-cell ST3Gal-1/Neu3 ratios in SLE and B-cell ST3Gal-1 and Neu3 levels in RA with high disease-activity DAS28 scores correlated with disease activity measures and may be useful in monitoring disease activities.

Genome-wide association study in NSAID-induced acute urticaria/angioedema in Spanish and Han Chinese populations.

AIM: Acute urticaria/angioedema (AUA) induced by cross-intolerance to NSAIDs is the most frequent clinical entity in hypersensitivity reactions to drugs. In this work, we conducted a genome-wide association study in Spanish and Han Chinese patients suffering from NSAID-induced AUA. MATERIALS & METHODS: A whole-genome scan was performed on a total of 232 cases (112 Spanish and 120 Han Chinese) with NSAID-induced AUA and 225 unrelated controls (124 Spanish and 101 Han Chinese). RESULTS: Although no polymorphism reached genome-wide significance, we obtained suggestive associations for three clusters in the Spanish group (RIMS1, BICC1 and RAD51L 1) and one region in the Han Chinese population (ABI3BP). Five regions showed suggestive associations after meta-analysis: HLF, RAD51L1, COL24A1, GalNAc-T13 and FBXL7. A majority of these genes are related to Ca(2+), cAMP and/or P53 signaling pathways. CONCLUSION: The associations described were different from those related to the metabolism of arachidonic acid and could provide new mechanisms underlying NSAID-induced AUA.

Blood monocyte chemotactic protein-1 (MCP-1) and adapted disease activity Score28-MCP-1: favorable indicators for rheumatoid arthritis activity.

OBJECTIVE: We assessed blood pentraxin 3 (PTX3) and macrophage chemotactic factor-1 (MCP-1) levels as indicators of disease activity in rheumatoid arthritis (RA) patients, because data on disease activity score 28 (DAS28)-erythrocyte sedimentation rate (ESR) and DAS28-C-reactive protein (CRP) are still imperfect. METHODS: In 111 patients with RA, we examined longitudinal and cross-sectional correlations of blood PTX3, MCP-1, CRP, and ESR levels with measures of clinical arthritic activity, namely, swollen joint count (SJC), tender joint count (TJC), visual analog scale for general health (GH), DAS28, and adapted DAS28-MCP-1. RESULTS: Blood MCP-1, but not PTX3, was significantly correlated with SJC, TJC, DAS28, and DAS28-CRP. DAS28-MCP-1 was strongly correlated with DAS28 (r  = 0.984, P<0.001) and DAS28-CRP (r  = 0.971, P<0.001), and modestly correlated with CRP (r  = 0.350, P<0.001), and ESR (r  = 0.386, P<0.001). Similarly, the duration of arthritic symptoms, but not sex, was significantly correlated with variables of arthritic activity. In particular, DAS28-MCP-1 significantly correlated with DAS28 during a 6-month period (r  = 0.944, P<0.001; r  = 0.951, P<0.001; r  = 0.862, P<0.001; and r  = 0.865, P<0.001 for month 0, 1, 3, and 6, respectively). CONCLUSION: Blood MCP-1 and adapted DAS28-MCP-1, but not blood PTX3, may be useful in monitoring RA activity.

Comparison of cryoglobulinemia in children and adults.

BACKGROUND/PURPOSE: Cryoglobulinemic vasculitis is a systemic vasculitis resulting from circulating immune complex deposition in the small vessels and is characterized by variable clinical features, including purpura, Raynaud's syndrome, ulcerations, arthralgia, glomerulonephritis, and peripheral neuropathy. Cryoglobulinemia can also result from hepatitis C virus (HCV) infection. The clinical spectrum and associated or underlying diseases of cryoglobulinemia in different age groups is not well understood. This study investigated the demographic, clinical, serologic features, and associated or underlying diseases in children and adult patients with cryoglobulinemia. METHODS: The retrospective study included 114 patients (18 children, 96 adults) who presented with cryoglobulinemia between 2000 and 2010 at the Chang Gung Memorial Hospital. Their medical records were reviewed and serological and virologic assessments were analyzed. RESULTS: In this group of patients, children had a significantly higher prevalence of prolonged fever (16.7% vs. 3.13%; p=0.018), arthralgia (66.67% vs. 16.67%; p<0.001), arthritis (66.67% vs. 15.63%; p<0.001) and cutaneous involvement (77.78% vs. 50%; p=0.03) compared with adults. Both the adult and children groups had a greater frequency of hepatitis B virus (HBV) infection (20.8% and 5.6%, respectively), than HCV infection (12.5% and 0%, respectively). CONCLUSIONS: Children with cryoglobulinemia had a significantly higher prevalence of prolonged fever, arthralgia, arthritis and cutaneous involvement compared with adults.

Infections in polymyositis and dermatomyositis: analysis of 192 cases.

OBJECTIVES: To estimate the incidence, characteristics and predictors of infections in patients with PM and DM. METHODS: The medical records of 192 PM/DM patients followed up in a tertiary teaching medical centre from 1999 to 2008 were retrospectively reviewed. RESULTS: Seventy-six episodes of major infection, defined as infections requiring>1 week of treatment with anti-microbial agents, occurred in 53 (27.6%) patients, and 15 (7.8%) patients had two or more episodes. The incidence rate of major infections was 11.1 episodes per 100 patient-years in PM/DM patients. Aspiration pneumonia [n (%)=16 (21.1)] was the leading cause of major infections, followed by opportunistic infection [n (%)=14 (18.4)]. A variety of pathogens were isolated, mainly including Staphylococcus aureus, Klebsiella, Escherichia coli, Salmonella and Mycobacterium. Overall patient survival rates were 85.0% at 1 year, 78.0% at 5 years and 78.0% at 10 years. However, after one episode of major infection, survival rates decreased to 84.7% at 30 days and 68.3% at 1 year. Multivariate analysis indicated that independent predictors of major infection were age>45 years at PM/DM onset [odds ratio (OR) 5.26; 95% CI 2.01, 13.77; P=0.001], presence of arthritis/arthalgia (OR 2.59; 95% CI 1.12, 6.02; P=0.027), co-present interstitial lung disease (OR 7.24; 95% CI 2.67, 19.65; P<0.001), current use of AZA (OR 6.07; 95% CI 2.39, 15.42; P<0.001) or IVIG (OR 6.33; 95% CI 1.50, 26.77; P=0.012). CONCLUSIONS: This study underlines the high frequency of major infections in PM/DM, which is significantly detrimental to patient survival rates. Close follow-up of PM/DM patients with risk factors for developing major infections is mandatory.

Better short-term clinical response to etanercept in Chinese than Caucasian patients with active ankylosing spondylitis.

Tumor necrosis factor-alpha (TNF-α) inhibitors including etanercept have been demonstrated to be very effective in severe ankylosing spondylitis (AS) in Caucasian patients. However, clinical efficacy of etanercept to treat active AS in Chinese patients has not been reported. In this study, a prospective, open-label trial of etanercept (25 mg BIW), involving 46 AS patients from 16 medical centers of Taiwan, was conducted. Questionnaire was utilized to record demographic data and clinical parameters, including Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), Bath AS Global Index (BASGI), Assessment in Ankylosing Spondylitis (ASAS) 20, 50, and 70, and others, before and at different time intervals after etanercept treatment. Laboratory tests including blood chemistry, hematology, urine analysis, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were done at baseline and at weeks 4, 8, and 12. In this 12-week study, etanercept demonstrated rapid and significant improvement in the ASAS20 response criteria (91.3%), at as early as 2 weeks of therapy (71.3%). Partial remission of AS was achieved in 49.3% of patients after 12 weeks of treatment. Disease activity (BASDAI) and function (BASFI) were also significantly improved after 12 weeks etanercept treatment (p < 0.0001 and p < 0.0001, respectively). In addition, significant increase of chest expansion (2.77 ± 1.69 cm versus 3.56 ± 1.82 cm, p = 0.0004) and lumbar flexion (2.11 ± 2.76 cm versus 2.58 ± 3.42 cm, p = 0.0075) and significant reduction of occiput-to-wall distance (6.59 ± 7.14 cm versus 5.32 ± 6.65 cm, p = 0.0006) were also demonstrated. Both ESR and CRP declined significantly after patients were treated with etanercept. There were no severe adverse effects during the treatment period. Etanercept is generally safe, well tolerated, and effective in Chinese patients with severe AS. Clinical efficacy, including partial remission and BASDAI, is even better in Chinese than in Caucasian patients. Further study is required to assess long-term efficacy and safety in Chinese patients with AS.

Changing cytokine patterns in systemic lupus: a prospective longitudinal study.

BACKGROUND/PURPOSE: We have previously reported that lupus monocytes display distinctively differing patterns of C-reactive protein (CRP)-inducing cytokine interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha secretion when stimulated with either immune complexes (ICs) or lipopolysaccharide (LPS). In this study, we investigated whether the cytokine patterns of peripheral blood mononuclear cells (PBMCs) isolated from lupus patients acquired an IC or LPS pattern, either over time, or following corticosteroid or hydroxychloroquine use. METHODS: PBMCs from lupus patients were obtained at 0, 1, 3, and 6 months post diagnosis and stimulated with ICs or LPS. Cells were obtained for polymerase chain reaction to determine the IL-6, IL-1beta, and TNF-alpha mRNA expression, and were assigned as having acquired either an IC or an LPS pattern. RESULTS: Upon stimulation, the mRNA expression levels of the IL-6 and IL-1beta were significantly higher in IC-pattern PBMCs than in LPS-pattern PBMCs (p= 0.021 and 0.028, respectively). Consistent with this, serum CRP levels in the IC-pattern group were significantly higher than those in the LPS-pattern groups (p = 0.027). Total serum CRP levels were positively correlated with serum C3c and C4 concentrations, and inversely correlated with serum anti-double stranded DNA (anti-dsDNA) levels. Conversely, circulating ICs were positively correlated with serum anti-dsDNA levels and inversely correlated with serum C4 concentrations. CONCLUSION: Within the same individual, the CRP-inducing cytokine patterns can be changed, either naturally or after medication. Pre-existing serum circulating ICs are not predisposed to either IC or LPS cytokine patterns. Finally, CRP levels were correlated with anti-dsDNA consumption.

Interstitial lung disease in polymyositis and dermatomyositis.

The aim of the study was to estimate the prevalence, characteristics, and prognostic factors of interstitial lung disease (ILD) in patients with polymyositis (PM) and dermatomyositis (DM). The medical records of 151 PM/DM patients treated at Chang Gung Memorial Hospital between January, 2000 and June, 2007 were retrospectively reviewed. Thirty of 151 (19.9%) PM/DM patients had developed ILD. Older age at PM/DM onset, anti-Jo-1 antibody, and arthritis/arthralgia were associated with the presence of ILD (p = 0.004, p = 0.008, and p = 0.026, respectively). Anti-Jo-1 was initially excluded from the multivariate analysis because only 80 patients underwent the test. An older age at onset above 45 years (odds ratio 3.28, 95% confidence interval (CI) 1.15-9.34, p = 0.026) and arthritis/arthralgia at onset (odds ratio (OR) 2.57, 95% CI 1.09-6.08, p = 0.032) were the two independent risk factors for developing ILD. If anti-Jo-1 was included in the multivariate analysis (n = 80), then an older age at onset above 45 years (OR 7.30, 95% CI 1.70-31.40, p = 0.008) and anti-Jo-1 positive (OR 7.89, 95% CI 1.18-52.87, p = 0.033) were associated with ILD, while arthritis/arthralgia was no longer significant (OR 2.64, 95% CI 0.70-10.01, p = 0.153). Of the 30 ILD patients, 16 (53.3%) died. The survival time was significantly shorter in ILD patients than in patients without ILD (p < 0.001). Poor survival in ILD patients was associated with male gender (p = 0.039), a Hamman-Rich-like presentation (p = 0.039), and a clinical diagnosis of acute interstitial pneumonia (p = 0.007).

Rare copresent rheumatoid arthritis and gout: comparison with pure rheumatoid arthritis and a literature review.

Copresent rheumatoid arthritis (RA) and gout is seldom reported. This study summarizes the findings of eight cases of copresent RA and gout and compares them with 31 pure RA cases. Additional reported cases were retrieved from the current literature by Medline search. Patients with copresent RA and gout were older (p = 0.014) and predominantly male (p < 0.01). Synovial fluid, positive for urate crystals, was aspirated most frequently from the knee (five out of eight), followed by the first metatarsophalangeal joint (three out of eight). Serum creatinine and urate levels in the copresent group were significantly higher (p < 0.01, both), and serum hemoglobin was lower (p = 0.04) than those with pure RA. Copresent subjects had much lower percentage of positive rheumatoid factor (RF) tests than patients with pure RA (37.5 vs 80.6%). Only one copresent subject had both RF and anti-cyclic citrullinated peptide antibody. Of copresent subjects, 75% had gouty arthritis before diagnosis of RA, which is consistent with earlier reports. Seven copresent subjects had gout attacks under disease-modifying antirheumatic drug use. This study revealed that polyarthritis negative for RF in a previously gouty patient may be RA and vice versa. This combination occurs more frequently in males. Moreover, anti-CCP antibody examination is not helpful for this diagnosis. Therefore, physicians must obtain synovial fluid for analysis in joints with intense swelling, especially in old RA subjects with renal insufficiency or involvement of lower extremities. Conversely, RA must be considered in gouty patients with polyarticular involvement.

Coexisting ankylosing spondylitis and gouty arthritis.

The aim of this study was to investigate the clinical characteristics of patients with coexisting ankylosing spondylitis (AS) and gout. Between July 1987, and October 2004, sixty-five patients with coexisting AS and gout were enrolled. The clinical manifestations of both AS and gout in these patients were studied. Of the 65 patients included in the study, 61 were men and four were women (men-to-women ratio, 15.3:1). Sixty-three subjects were Han Chinese, and two were Atayal Aborigines. Mean ages at onset of AS and gout were 29.3 +/- 15.6 years (range 7-63) and 42.2 +/- 13.2 years (range 20-74), respectively. Fifty-six patients developed gout after (15.5 +/- 11.2 years; range, 1-51 years) onset of AS; nine patients developed gout before (average, 3.4 +/- 2.2 years; range. 1-7 years) onset of AS. Forty-four (67.7%) patients had chronic peripheral arthritis and all 65 (100%) patients had acute peripheral arthritis. Thirty-three (50.8%) cases had heel pain (enthesopathy), including 22 (33.9%) with chronic heel pain, seven (10.8%) with acute heel pain, and four (6.2%) with concurrent acute and chronic heel pain. Sixty-one (93.9%) subjects were HLA-B27 antigen positive. Medical conditions potentially associated with hyperuricemia or gout were urolithiasis (n = 17), hypertension (n = 21), diabetes mellitus (n = 8), hyperlipidemia (n = 34), congestive heart failure (n = 6), coronary heart disease (n = 5), and stroke (n = 3). The following drugs were prescribed: diuretics (n = 7), low-dose aspirin (n = 4), antituberculous drugs (n = 1), and sulphasalazine (n = 34). Six (6.2%) patients had iatrogenic Cushing syndrome with adrenal insufficiency. Patients with coexisting AS and gout are not rare. Distinguishing between peripheral arthritis or enthesopathies of AS and gout is essential, especially when the course of AS arthritis becomes acute or the course of gout becomes chronic.

HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol.

Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol-SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol-SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol-SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) (P < 10(-7)). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-SCAR, but only in 20 (15%) of 135 tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4-9780.9); corrected P value = 4.7 x 10(-24)] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23-6665.26); corrected P value = 8.1 x 10(-18)]. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.