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Research paper thumbnail of <i>IL-1B</i> and <i>IL-1RN</i> gene polymorphisms in rheumatoid arthritis: relationship with protein plasma levels and response to therapy

Pharmacogenomics, Jul 1, 2006

Objectives: To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibili... more Objectives: To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibility to, and severity of, rheumatoid arthritis (RA) patients, comparing them with the genotype distribution in healthy controls. Also, to assess the influence of IL1-B and IL1RN gene polymorphism on IL-1β/IL-1Ra plasma levels and response to therapy. Patients and methods: We tested the allelic distribution of IL-1B (-511 and +3953) and IL-1RN (variable number of tandem repeats) gene polymorphism in 126 RA patients and 178 healthy blood donors (HBDs). The patients were categorized into two subgroups in relation to the response to methotrexate (MTX) therapy. Group A included 70 RA patients in stable partial remission after 6 months of MTX treatment (MTX-R). Group B included 56 RA patients with active disease despite MTX therapy. This group received antitumor necrosis factor (TNF) biological drugs and were defined MTX-nonresponders (MTX-NR). Results: None of the two IL-1B (-511 and +3953) gene polymorphisms were significantly different in frequency between RA patients and healthy controls. We observed an increased frequency of the rare allele IL1RN*3 in RA patients with active disease, not responding to MTX therapy (MTX-NR) (4.5%) vs MTX-R (3.6%) and healthy controls (0.8%). Interestingly, RA patients whose genotypes included the IL1RN*long allele (haplotype long-C-T) showed the worse response to MTX. HBDs harboring the IL1RN*2/2 genotype showed significantly lower levels of plasma IL1-Ra, but comparable levels of IL-1β with regard to subjects with the presence of the IL1RN* long allele. Furthermore, the presence of the TT IL-1B +3953 genotype was associated with lower plasma levels of IL1-Ra, both in HBDs and in RA patients. Carriers of the IL1RN*2 allele responded better to infliximab therapy. Conclusions: The results of this study provide evidence of an association between the IL1RN*long allele and RA, the strongest association being observed in RA patients with an aggressive disease resistant to MTX treatment.

Research paper thumbnail of Major

Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-dept... more Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-depth statistical analysis of the

Research paper thumbnail of Major

Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-dept... more Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-depth statistical analysis of the

Research paper thumbnail of Levels, Clinical Disease Activity, and Response to Treatment in Early Rheumatoid Arthritis

Research paper thumbnail of IP ルータによる帯域占有度の高いフロー検出制御機構の実装と評価(特集●インターネット)

Research paper thumbnail of Concentrations of BAFF correlate with autoantibody levels, clinical disease activity, and response to treatment in early rheumatoid arthritis

The Journal of rheumatology, 2008

To determine whether levels of B cell activating factor (BAFF), a member of the tumor necrosis fa... more To determine whether levels of B cell activating factor (BAFF), a member of the tumor necrosis factor family, relate to autoantibody levels, disease activity, and response to treatment in patients with early rheumatoid arthritis (ERA). BAFF was measured by ELISA in 48 early RA patients; 21 were examined serially. These data were compared with 49 controls with longstanding RA (LSRA), 48 disease controls (DC), and 50 healthy controls (HC). BAFF levels were higher in ERA, compared with DC and HC [median 4.3 ng/ml (5th-95th: 0.8-38.8) vs 0.9 ng/ml (5th-95th: 0.7-4.5) and 2.0 ng/ml (5th-95th: 0.7-5.68), respectively; p <10(-4 )both comparisons], but not with LSRA controls [median 8.7 ng/ml (5th-95th: 0.8-46.1); p = nonsignificant]. BAFF correlated with the titers of IgM rheumatoid factor and anti-cyclic citrullinated peptide autoantibody (r = 0.76 and r = 0.49; p < 0.00001, p = 0.0001 for the 2 correlations), and with the number of swollen joints (r = 0.37; p = 0.01). The followup ...

Research paper thumbnail of Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-depth statistical analysis of the major outcome

Rheumatology, 2009

Objective. To obtain the simplest definition of minimal disease activity (MDA) and to compare it ... more Objective. To obtain the simplest definition of minimal disease activity (MDA) and to compare it with published proposed definitions of MDA in patients with RA. Methods. Two hundred and fourteen patients with long-standing RA (LSRA) were evaluated for clinical and laboratory parameters. Factor analysis was performed to remove redundant variables included in the core set measure for MDA definition stated by the OMERACT. Receiver operating characteristic (ROC) curves analysis allowed to obtain optimal cutoff predictors of a 28-joint disease activity score (DAS28) 42.85. These were tested in 112 LSRA and 95 early-onset RA (ERA) patients. Results. Factor and ROC curve analysis showed that the best predictors of a DAS28 4 2.85 in LSRA cohort were: (i) ESR <20 mm/h (sensitivity: 80%, specificity: 54%); (ii) swollen joint count (out of 28) 42 (sensitivity: 95%, specificity: 74%); (iii) patient global assessment (0-100) 415 (sensitivity: 78%, specificity: 78%); and (iv) HAQ (0-3) 40.5 (sensitivity: 91%, specificity: 61%). To each of these four criteria we assigned a value of 1 when it was satisfied (score ranging: 0-4). The cutoff with the highest overall accuracy for identifying RA patients with DAS28 4 2.85 was a score 53. We adopted these four parameters in order to define the residual MDA (RMDA). Comparing RMDA criteria, in distinct 112 LSRA and 95 ERA patients, with OMERACT, Simplified Disease Activity Index and Clinical Disease Activity Index definitions of MDA, we found a good agreement in the LSRA cohort and moderate agreement in the ERA cohort. Conclusions. HAQ, PaGA, SJC28 and ESR allow identification of RA patients with an RMDA. The RMDA criteria behaves similarly to OMERACT definitions, but appears more simple and feasible.

Research paper thumbnail of IL-1B and IL-1RN gene polymorphisms in rheumatoid arthritis: relationship with protein plasma levels and response to therapy

Pharmacogenomics, 2006

Objectives: To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibili... more Objectives: To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibility to, and severity of, rheumatoid arthritis (RA) patients, comparing them with the genotype distribution in healthy controls. Also, to assess the influence of IL1-B and IL1RN gene polymorphism on IL-1β/IL-1Ra plasma levels and response to therapy. Patients and methods: We tested the allelic distribution of IL-1B (-511 and +3953) and IL-1RN (variable number of tandem repeats) gene polymorphism in 126 RA patients and 178 healthy blood donors (HBDs). The patients were categorized into two subgroups in relation to the response to methotrexate (MTX) therapy. Group A included 70 RA patients in stable partial remission after 6 months of MTX treatment (MTX-R). Group B included 56 RA patients with active disease despite MTX therapy. This group received antitumor necrosis factor (TNF) biological drugs and were defined MTX-nonresponders (MTX-NR). Results: None of the two IL-1B (-511 and +3953) gen...

Research paper thumbnail of Allele *2 of the HS1,2A enhancer of the Ig regulatory region associates with rheumatoid arthritis

Annals of the Rheumatic Diseases, 2009

Objective:To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker f... more Objective:To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker for rheumatoid arthritis (RA) and to define the possible association with autoantibody positivity and clinical outcome.Methods:Genomic DNA was obtained from two cohorts of patients with RA (100 with early RA (ERA) and 114 with longstanding RA (LSRA)) and from 248 gender-matched controls from the same geographical area. Clinical and immunological characteristics were recorded for all the patients.Results:The percentage of the 2/2 genotype was higher in patients with ERA (27.0%), and in patients with LSRA (34.2%), than in controls (14.9%) (ERA: OR = 2.11 (95% CI 1.20 to 3.70) vs controls; LSRA: OR = 2.96 (95% CI 1.76 to 5.00) vs controls). A lower representation of allele *3 was present in patients with ERA (2.0%) than in controls (6.0%; OR = 0.32 (95% CI 0.11 to 0.91)). No significant associations were found between polymorphisms and autoantibodies positivity.Conclusion:The HS1,2A allele *...

Research paper thumbnail of Diagnostic performance of anti-citrullinated peptide antibodies for the diagnosis of rheumatoid arthritis: the relevance of likelihood ratios

Clinical Chemistry and Laboratory Medicine, 2010

The prevalence rates of anti-citrullinated protein/peptide antibodies (ACPAs) were investigated i... more The prevalence rates of anti-citrullinated protein/peptide antibodies (ACPAs) were investigated in a cohort of juvenile idiopathic arthritis (JIA) patients, and their diagnostic performances were compared. ACPAs, including anti-cyclic citrullinated peptide IgG (anti-CCP), anti-CCP IgG/IgA (anti-CCP3.1), citrullinated recombinant rat filaggrin antibodies (CPA), anti-mutated citrullinated vimentin (anti-MCV), and antibodies to citrullinated human IgG-derived peptides (RA/CP), were measured in the sera from 81 JIA patients. Serum samples from 55 children with other joint diseases or viral infections and 49 healthy donors were tested as controls. Of the 81 JIA patients, 7 (8.6%), 8 (9.9%), 17 (21.0%), 23 (28.4%), and 18 (22.2%) were found to be positive for anti-CCP, anti-CCP3.1, CPA, anti-MCV, and RA/CP, respectively, with specificities of 98.1, 95.1, 93.3, 84.6, and 86.5%. Analysis by subtype revealed that 7/7 (100%) of RF-positive polyarticular JIA patients tested positive at high serum levels for anti-©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 15 (2): gmr.15028641 MCV or RA/CP, and 5/7 (71.4%) were positive for anti-CCP, anti-CCP3.1, or CPA (P < 0.001, compared with controls). Eighteen of 81 JIA patients demonstrated joint erosions on radiographs and erosive arthritis occurred more often in ACPAs positive patients (P < 0.01). Our findings indicate that although ACPAs are not satisfactory screening biomarkers for JIA due to low sensitivity, ACPA measurement can aid in diagnosing RF-positive polyarticular JIA and identifying JIA patients with severe bone involvement. The diagnostic performance of each ACPA in JIA is different, and the careful selection of assays is necessary.

Research paper thumbnail of <i>IL-1B</i> and <i>IL-1RN</i> gene polymorphisms in rheumatoid arthritis: relationship with protein plasma levels and response to therapy

Pharmacogenomics, Jul 1, 2006

Objectives: To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibili... more Objectives: To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibility to, and severity of, rheumatoid arthritis (RA) patients, comparing them with the genotype distribution in healthy controls. Also, to assess the influence of IL1-B and IL1RN gene polymorphism on IL-1β/IL-1Ra plasma levels and response to therapy. Patients and methods: We tested the allelic distribution of IL-1B (-511 and +3953) and IL-1RN (variable number of tandem repeats) gene polymorphism in 126 RA patients and 178 healthy blood donors (HBDs). The patients were categorized into two subgroups in relation to the response to methotrexate (MTX) therapy. Group A included 70 RA patients in stable partial remission after 6 months of MTX treatment (MTX-R). Group B included 56 RA patients with active disease despite MTX therapy. This group received antitumor necrosis factor (TNF) biological drugs and were defined MTX-nonresponders (MTX-NR). Results: None of the two IL-1B (-511 and +3953) gene polymorphisms were significantly different in frequency between RA patients and healthy controls. We observed an increased frequency of the rare allele IL1RN*3 in RA patients with active disease, not responding to MTX therapy (MTX-NR) (4.5%) vs MTX-R (3.6%) and healthy controls (0.8%). Interestingly, RA patients whose genotypes included the IL1RN*long allele (haplotype long-C-T) showed the worse response to MTX. HBDs harboring the IL1RN*2/2 genotype showed significantly lower levels of plasma IL1-Ra, but comparable levels of IL-1β with regard to subjects with the presence of the IL1RN* long allele. Furthermore, the presence of the TT IL-1B +3953 genotype was associated with lower plasma levels of IL1-Ra, both in HBDs and in RA patients. Carriers of the IL1RN*2 allele responded better to infliximab therapy. Conclusions: The results of this study provide evidence of an association between the IL1RN*long allele and RA, the strongest association being observed in RA patients with an aggressive disease resistant to MTX treatment.

Research paper thumbnail of Major

Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-dept... more Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-depth statistical analysis of the

Research paper thumbnail of Major

Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-dept... more Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-depth statistical analysis of the

Research paper thumbnail of Levels, Clinical Disease Activity, and Response to Treatment in Early Rheumatoid Arthritis

Research paper thumbnail of IP ルータによる帯域占有度の高いフロー検出制御機構の実装と評価(特集●インターネット)

Research paper thumbnail of Concentrations of BAFF correlate with autoantibody levels, clinical disease activity, and response to treatment in early rheumatoid arthritis

The Journal of rheumatology, 2008

To determine whether levels of B cell activating factor (BAFF), a member of the tumor necrosis fa... more To determine whether levels of B cell activating factor (BAFF), a member of the tumor necrosis factor family, relate to autoantibody levels, disease activity, and response to treatment in patients with early rheumatoid arthritis (ERA). BAFF was measured by ELISA in 48 early RA patients; 21 were examined serially. These data were compared with 49 controls with longstanding RA (LSRA), 48 disease controls (DC), and 50 healthy controls (HC). BAFF levels were higher in ERA, compared with DC and HC [median 4.3 ng/ml (5th-95th: 0.8-38.8) vs 0.9 ng/ml (5th-95th: 0.7-4.5) and 2.0 ng/ml (5th-95th: 0.7-5.68), respectively; p <10(-4 )both comparisons], but not with LSRA controls [median 8.7 ng/ml (5th-95th: 0.8-46.1); p = nonsignificant]. BAFF correlated with the titers of IgM rheumatoid factor and anti-cyclic citrullinated peptide autoantibody (r = 0.76 and r = 0.49; p < 0.00001, p = 0.0001 for the 2 correlations), and with the number of swollen joints (r = 0.37; p = 0.01). The followup ...

Research paper thumbnail of Residual minimal disease activity in rheumatoid arthritis: a simple definition through an in-depth statistical analysis of the major outcome

Rheumatology, 2009

Objective. To obtain the simplest definition of minimal disease activity (MDA) and to compare it ... more Objective. To obtain the simplest definition of minimal disease activity (MDA) and to compare it with published proposed definitions of MDA in patients with RA. Methods. Two hundred and fourteen patients with long-standing RA (LSRA) were evaluated for clinical and laboratory parameters. Factor analysis was performed to remove redundant variables included in the core set measure for MDA definition stated by the OMERACT. Receiver operating characteristic (ROC) curves analysis allowed to obtain optimal cutoff predictors of a 28-joint disease activity score (DAS28) 42.85. These were tested in 112 LSRA and 95 early-onset RA (ERA) patients. Results. Factor and ROC curve analysis showed that the best predictors of a DAS28 4 2.85 in LSRA cohort were: (i) ESR <20 mm/h (sensitivity: 80%, specificity: 54%); (ii) swollen joint count (out of 28) 42 (sensitivity: 95%, specificity: 74%); (iii) patient global assessment (0-100) 415 (sensitivity: 78%, specificity: 78%); and (iv) HAQ (0-3) 40.5 (sensitivity: 91%, specificity: 61%). To each of these four criteria we assigned a value of 1 when it was satisfied (score ranging: 0-4). The cutoff with the highest overall accuracy for identifying RA patients with DAS28 4 2.85 was a score 53. We adopted these four parameters in order to define the residual MDA (RMDA). Comparing RMDA criteria, in distinct 112 LSRA and 95 ERA patients, with OMERACT, Simplified Disease Activity Index and Clinical Disease Activity Index definitions of MDA, we found a good agreement in the LSRA cohort and moderate agreement in the ERA cohort. Conclusions. HAQ, PaGA, SJC28 and ESR allow identification of RA patients with an RMDA. The RMDA criteria behaves similarly to OMERACT definitions, but appears more simple and feasible.

Research paper thumbnail of IL-1B and IL-1RN gene polymorphisms in rheumatoid arthritis: relationship with protein plasma levels and response to therapy

Pharmacogenomics, 2006

Objectives: To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibili... more Objectives: To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibility to, and severity of, rheumatoid arthritis (RA) patients, comparing them with the genotype distribution in healthy controls. Also, to assess the influence of IL1-B and IL1RN gene polymorphism on IL-1β/IL-1Ra plasma levels and response to therapy. Patients and methods: We tested the allelic distribution of IL-1B (-511 and +3953) and IL-1RN (variable number of tandem repeats) gene polymorphism in 126 RA patients and 178 healthy blood donors (HBDs). The patients were categorized into two subgroups in relation to the response to methotrexate (MTX) therapy. Group A included 70 RA patients in stable partial remission after 6 months of MTX treatment (MTX-R). Group B included 56 RA patients with active disease despite MTX therapy. This group received antitumor necrosis factor (TNF) biological drugs and were defined MTX-nonresponders (MTX-NR). Results: None of the two IL-1B (-511 and +3953) gen...

Research paper thumbnail of Allele *2 of the HS1,2A enhancer of the Ig regulatory region associates with rheumatoid arthritis

Annals of the Rheumatic Diseases, 2009

Objective:To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker f... more Objective:To investigate the role of the HS1,2 enhancer polymorphisms as a new candidate marker for rheumatoid arthritis (RA) and to define the possible association with autoantibody positivity and clinical outcome.Methods:Genomic DNA was obtained from two cohorts of patients with RA (100 with early RA (ERA) and 114 with longstanding RA (LSRA)) and from 248 gender-matched controls from the same geographical area. Clinical and immunological characteristics were recorded for all the patients.Results:The percentage of the 2/2 genotype was higher in patients with ERA (27.0%), and in patients with LSRA (34.2%), than in controls (14.9%) (ERA: OR = 2.11 (95% CI 1.20 to 3.70) vs controls; LSRA: OR = 2.96 (95% CI 1.76 to 5.00) vs controls). A lower representation of allele *3 was present in patients with ERA (2.0%) than in controls (6.0%; OR = 0.32 (95% CI 0.11 to 0.91)). No significant associations were found between polymorphisms and autoantibodies positivity.Conclusion:The HS1,2A allele *...

Research paper thumbnail of Diagnostic performance of anti-citrullinated peptide antibodies for the diagnosis of rheumatoid arthritis: the relevance of likelihood ratios

Clinical Chemistry and Laboratory Medicine, 2010

The prevalence rates of anti-citrullinated protein/peptide antibodies (ACPAs) were investigated i... more The prevalence rates of anti-citrullinated protein/peptide antibodies (ACPAs) were investigated in a cohort of juvenile idiopathic arthritis (JIA) patients, and their diagnostic performances were compared. ACPAs, including anti-cyclic citrullinated peptide IgG (anti-CCP), anti-CCP IgG/IgA (anti-CCP3.1), citrullinated recombinant rat filaggrin antibodies (CPA), anti-mutated citrullinated vimentin (anti-MCV), and antibodies to citrullinated human IgG-derived peptides (RA/CP), were measured in the sera from 81 JIA patients. Serum samples from 55 children with other joint diseases or viral infections and 49 healthy donors were tested as controls. Of the 81 JIA patients, 7 (8.6%), 8 (9.9%), 17 (21.0%), 23 (28.4%), and 18 (22.2%) were found to be positive for anti-CCP, anti-CCP3.1, CPA, anti-MCV, and RA/CP, respectively, with specificities of 98.1, 95.1, 93.3, 84.6, and 86.5%. Analysis by subtype revealed that 7/7 (100%) of RF-positive polyarticular JIA patients tested positive at high serum levels for anti-©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 15 (2): gmr.15028641 MCV or RA/CP, and 5/7 (71.4%) were positive for anti-CCP, anti-CCP3.1, or CPA (P < 0.001, compared with controls). Eighteen of 81 JIA patients demonstrated joint erosions on radiographs and erosive arthritis occurred more often in ACPAs positive patients (P < 0.01). Our findings indicate that although ACPAs are not satisfactory screening biomarkers for JIA due to low sensitivity, ACPA measurement can aid in diagnosing RF-positive polyarticular JIA and identifying JIA patients with severe bone involvement. The diagnostic performance of each ACPA in JIA is different, and the careful selection of assays is necessary.