Four-year follow-up of infliximab therapy in rheumatoid arthritis patients with long-standing refractory disease: attrition and long-term evolution of disease activity

Although there is strong evidence supporting the short-term efficacy and safety of anti-tumour necrosis factor-alpha agents, few studies have examined the long-term effects. We evaluated 511 patients with long-standing refractory rheumatoid arthritis treated with intravenous infusions of infliximab 3 mg/kg at weeks 0, 2, 6, and 14 and every 8 weeks thereafter for 4 years. Among the initial 511 patients included in the study, 479 could be evaluated; of these, 295 (61.6%) were still receiving infliximab treatment at year 4 of follow-up. The most common reasons for treatment discontinuation were lack of efficacy (65 patients, 13.6%), safety (81 patients, 16.9%), and elective change (38 patients, 7.9%). Analysis of disease activity scores (DAS28 [disease activity score based on the 28-joint count]) over time showed that, after the initial rapid improvement during the first 6 to 22 weeks of therapy, a further decrease in disease activity of 0.2 units in the DAS28 score per year was observed. DAS28 scores, measured at week 14 or 22, were found to predict subsequent discontinuation due to lack of efficacy. In conclusion, long-term maintenance therapy with infliximab 3 mg/kg is effective in producing further reductions in disease activity. Disease activity measured by the DAS28 at week 14 or 22 of infliximab therapy was the best predictor of long-term attrition.     

Discontinuation of adalimumab after attaining disease activity score 28-erythrocyte sedimentation rate remission in patients with rheumatoid arthritis (HONOR study): an observational study

Introduction

Evidences of biologics-free disease control after discontinuing adalimumab (ADA) in rheumatoid arthritis (RA) patients in clinical practice have not been sufficiently investigated. Purpose of this study is to investigate whether disease activity score 28 (DAS28)- erythrocyte sedimentation rate (ESR) remission was preserved after discontinuation of ADA in patients with RA.

Methods

This is an observational but not a randomized controlled study. Among 197 RA patients who initiated with combination of ADA with concomitant MTX, 69 (35%) acquired DAS28 (ESR) < 2.6 for at least 24 weeks. Of those 69 patients, 51 went on ADA discontinuation with their consent, and finally 50 of those with follow-up of > 24 weeks were evaluated. The effect of discontinuing ADA on clinical disease activity, functional disability and radiographic progression were evaluated by DAS28 (ESR), the clinical disease activity index (CDAI) and the simplified disease activity index (SDAI), by a health assessment questionnaire-disability index (HAQ-DI) and by the modified total Sharp score (mTSS), respectively.

Results

The mean age of the participants was 59.5 years with the mean disease duration of 7.1 years. Out of the 50 patients, 29 (58%) were maintained in DAS28 (ESR) < 2.6 at 24 weeks after discontinuing ADA. A logistic regression analysis showed that DAS28 (ESR) at baseline significantly predicted a DAS28 (ESR) < 2.6 maintained after discontinuation of ADA, and a receiver-operating characteristic (ROC) analysis showed that the cut-off value of DAS28 (ESR) at discontinuation was 2.16. The mean HAQ-DI at six months after discontinuing ADA was 0.1 in patients who kept in DAS28 (ESR) < 2.6, and 94.9% (37/39) showed no evidence of radiographic progression (> 0.5 per year of a change in mTSS) at 1 year.

Conclusions

It was possible to maintain DAS28 (ESR) < 2.6 after discontinuation of ADA without functional and radiographic progression and very low DAS28 (ESR) at the discontinuation was associated with successful ADA-free DAS28 (ESR) < 2.6 in patients with RA.

Trial registration

University Hospital Medical Information Network Identifier: UMIN000006669.     

Determining a low disease activity threshold for decision to maintain disease-modifying antirheumatic drug treatment unchanged in rheumatoid arthritis patients

Introduction

The aim of this study was to determine a low disease activity threshold - a 28-joint disease activity score (DAS28) value - for the decision to maintain unchanged disease-modifying antirheumatic drug (DMARD) treatment in rheumatoid arthritis patients, based on expert opinion.

Methods

Nine hundred and sixty-seven case scenarios with various levels for each component of the DAS28 (resulting in a disease activity score between 2 and 3.2) were presented to 44 panelists. For each scenario, panelists had to decide whether or not DMARD treatment (excluding steroids) could be maintained unchanged. In each scenario, for decision, the participants were given the DAS28 parameters, without knowledge of the resultant DAS28. The relationship between panelists' decision, DAS28 value, and components of the score were analysed by multiple logistic regression analysis. Each panelist analysed 160 randomised scenarios. Intra-rater and inter-rater reproducibility were assessed.

Results

Forty-four panelists participated in the study. Inter-panelist agreement was good (κ = 0.63; 95% confidence interval = 0.61 to 0.65). Intra-panelist agreement was excellent (κ = 0.87; 95% confidence interval = 0.82 to 0.92). Quasi-perfect agreement was observed for DAS28 ≤ 2.4, less pronounced between 2.5 and 2.9, and almost no agreement for DAS28 > 3.0. For values below 2.5, panelists agreed to maintain unchanged DMARDs; for values above 2.5, discrepancies occurred more frequently as the DAS28 value increased. Multivariate analysis confirmed the relationship between panelist's decision, DAS28 value and components of the DAS28. Between DAS28 of 2.4 and 3.2, a major determinant for panelists' decision was swollen joint count. Female and public practice physicians decided more often to maintain treatment unchanged.

Conclusions

As a conclusion, panelists suggested that in clinical practice there is no need to change DMARD treatment in rheumatoid arthritis patients with DAS28 ≤ 2.4.     

Defining cut-off values for disease activity states and improvement scores for patient-reported outcomes: the example of the Rheumatoid Arthritis Impact of Disease (RAID)

Introduction

The Rheumatoid Arthritis Impact of Disease (RAID) is a patient-reported outcome measure evaluating the impact of rheumatoid arthritis (RA) on patient quality of life. It comprises 7 domains that are evaluated as continuous variables from 0 (best) to 10 (worst). The objective was to define and identify cut-off values for disease activity states as well as improvement scores in order to present results at the individual level (for example, patient in acceptable state, improved patient).

Methods

Patients with definite active RA requiring anti-tumour necrosis factor (anti-TNF) therapy were seen at screening, baseline and after 4 and 12 weeks of etanercept therapy. Answers to "Gold standard" questions on improvement (MCII: Minimum Clinically Important Improvement) and an acceptable status (PASS: Patient Acceptable Symptom State) were collected as well as the RAID score and Disease Activity Score 28- erythrocyte sedimentation rate (DAS28-ESR). Cut-offs were defined by different techniques including empirical, measurement error and gold standard anchors. The external validity of these cut-offs was evaluated using the positive likelihood ratio (LR) based on the patient's perspective (for example, patient's global) and on low disease activity status (such as DAS28-ESR).

Results

Ninety-seven (97) of the 108 recruited patients (age: 54 ± 13 years old, female gender: 75%, rheumatoid factor positive: 81%, disease duration: 8 ± 7 years, CRP: 18 ± 30 mg/l, DAS28-ESR: 5.4 ± 0.8) completed the 12 weeks of the study. The different techniques suggested thresholds ranging from 0.2 to 3 (absolute change) and from 6 to 50% (relative change) for defining MCII and thresholds from less than 1 to less than 4.2 for defining PASS. The evaluation of external validity (LR+) showed the highest LR+ was obtained with thresholds of 3 for absolute change; 50% for relative change and less than 2 for an acceptable status.

Conclusions

This study showed that thresholds defined for continuous variables are closely related to the methodological technique, justifying a systematic evaluation of their validity. Our results suggested that a change of at least 3 points (absolute) or 50% (relative) in the RAID score should be used to define a MCII and that a maximal value of 2 defines an acceptable status.

Trial Registration

Clinicaltrial.gov: NCT004768053     

Remission in psoriatic arthritis: is it possible and how can it be predicted?

Introduction

Since remission is now possible in psoriatic arthritis (PsA) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha (TNFα) therapy and to examine possible predictors of response.

Methods

Analysis of a prospective patient cohort attending a biologic clinic, between November 2004 and March 2008, was performed prior to commencing therapy and at regular intervals. Baseline clinical characteristics including demographics, previous disease-modifying antirheumatic drug (DMARD) response, tender and swollen joint counts, early morning stiffness, pain visual analogue score, patient global assessment, C reactive protein (CRP) and health assessment questionnaire (HAQ) were collected.

Results

A total of 473 patients (152 PsA; 321 rheumatoid arthritis (RA)) were analyzed. At 12 months remission, defined according to the disease activity score using 28 joint count and CRP (DAS28-CRP), was achieved in 58% of PsA patients compared to 44% of RA patients, significant improvement in outcome measures were noted in both groups (P < 0.05). Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission. Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients (P < 0.001).

Conclusions

DAS28 remission is possible in PsA patients at one year following anti-TNF therapy, at higher rates than in RA patients and is predicted by baseline HAQ.     

Semaphorin 3A is a marker for disease activity and a potential immunoregulator in systemic lupus erythematosus

Introduction

Higher levels of high density lipoprotein (HDL) subfractions HDL3-chol and particularly HDL2-chol protect against cardiovascular disease (CVD), but inflammation reduces the HDL level and may impair its anti-atherogenic effect. Changed HDL composition through the impact of inflammation on HDL subfractions may contribute to the excess risk of CVD in rheumatoid arthritis (RA). In this study, we investigated whether HDL2-chol and HDL3-chol concentrations differ between RA patients and healthy controls, and whether these levels are related to the level of RA disease activity.

Methods

Non-fasting blood samples were collected from 45 RA patients and 45 healthy controls. None of the participants had a history of CVD, diabetes, or used lipid-lowering drugs. HDL2-chol and HDL3-chol concentrations were obtained by ultracentrifugation. Regression modeling was used to compare HDL subfraction levels between RA patients and healthy controls, and to analyze the effect of disease activity on HDL2-chol and HDL3-chol.

Results

HDL2-chol and HDL3-chol were significantly lower in RA patients compared to healthy controls (P = 0.01, P = 0.005, respectively). The HDL2:HDL3 ratio was significantly lower in patients compared to controls (P = 0.04). Reduced HDL2-chol and HDL3-chol levels were primarily present in female RA patients and not in male RA patients. A modest effect of the disease activity score in 28 joins ( DAS28) on HDL2-chol concentrations was found, after correction for disease duration, glucocorticosteroid use and body mass index (BMI), with a 0.06 mmol/L decrease with every point increase in DAS28 (P = 0.05). DAS28 did not significantly affect HDL3-chol concentrations (P = 0.186).

Conclusions

Both HDL subfractions but particularly HDL2-chol concentrations were decreased in RA, primarily in women. This seems to be associated with disease activity and is of clinical relevance. The reduction of the HDL subfraction concentrations, particularly the supposedly beneficial HDL2-chol, may negatively impact the cardiovascular risk profile of women with RA.     

Expression of K2P5.1 potassium channels on CD4+ T lymphocytes correlates with disease activity in rheumatoid arthritis patients

Introduction

CD4⁺ T cells express K_2P5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K_2P5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K_2P5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients.

Methods

Expression levels of K_2P5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K_2P5.1.

Results

K_2P5.1 expression levels in CD4⁺ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K_2P5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K_2P5.1 expression to disease activity parameters during a longitudinal follow-up for six months.

Conclusions

Disease activity in RA patients correlates strongly with K_2P5.1 expression levels in CD4⁺ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K_2P5.1 as a potential biomarker for disease activity and differential diagnosis.     

Change in CD3 positive T-cell expression in psoriatic arthritis synovium correlates with change in DAS28 and magnetic resonance imaging synovitis scores following initiation of biologic therapy - a single centre, open-label study

Introduction

With the development of increasing numbers of potential therapeutic agents in inflammatory disease comes the need for effective biomarkers to help screen for drug efficacy and optimal dosing regimens early in the clinical trial process. This need has been recognized by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) group, which has established guidelines for biomarker validation. To seek a candidate synovial biomarker of treatment response in psoriatic arthritis (PsA), we determined whether changes in immunohistochemical markers of synovial inflammation correlate with changes in disease activity scores assessing 28 joints (ΔDAS28) or magnetic resonance imaging synovitis scores (ΔMRI) in patients with PsA treated with a biologic agent.

Methods

Twenty-five consecutive patients with PsA underwent arthroscopic synovial biopsies and MRI scans of an inflamed knee joint at baseline and 12 weeks after starting treatment with either anakinra (first 10 patients) or etanercept (subsequent 15 patients) in two sequential studies of identical design. DAS28 scores were measured at both time points. Immunohistochemical staining for CD3, CD68 and Factor VIII (FVIII) was performed on synovial samples and scored by digital image analysis (DIA). MRI scans performed at baseline and at 12 weeks were scored for synovitis semi-quantitatively. The ΔDAS28 of the European League Against Rheumatism good response definition (>1.2) was chosen to divide patients into responder and non-responder groups. Differences between groups (Mann Whitney U test) and correlations between ΔDAS28 with change in immunohistochemical and MRI synovitis scores (Spearman's rho test) were calculated.

Results

Paired synovial samples and MRI scans were available for 21 patients (8 anakinra, 13 etanercept) and 23 patients (8 anakinra, 15 etanercept) respectively. Change in CD3 (ΔCD3) and CD68 expression in the synovial sublining layer (ΔCD68sl) was significantly greater in the disease responders compared to non-responders following treatment (P = 0.005 and 0.013 respectively). ΔCD3, but not ΔCD68 or ΔFVIII, correlated with both ΔDAS28 (r = 0.49, P = 0.025) and ΔMRI (r = 0.58, P = 0.009).

Conclusions

The correlation of ΔCD3 with ΔDAS28 and ΔMRI following biologic treatment in this cohort contributes to the validation of ΔCD3 as a synovial biomarker of disease response in PsA, and supports the further evaluation of ΔCD3 for predictive properties of future clinical outcomes.     

Relationship between patient-reported disease severity in osteoarthritis and self-reported pain, function and work productivity

Introduction

The purpose of this study was theevaluation of synovial effusion (SE), synovial fluid (SF) and synovial tissue (ST) biomarkers in relation to disease activity indexes to assess the response to intraarticular (IA) tumor necrosis factor (TNF)-α blockers in psoriatic arthritis (PsA).

Methods

Systemic and local disease activity indexes (disease activity score (DAS); the Ritchie articular index (mRAI), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); Thompson articular (THOMP) and joint articular (KJAI)-Index ) and ST samples were assessed at baseline, throughout treatment, and during the follow-up in 14 patients affected with PsA who underwent IA injections (0.5 ml to 12.5 mg) in the knee joint of etanercept (E) or placebo (P) once every two weeks for a 10-week period. Total SF white blood cell (WBC) counts (WBC/μl) and SF cytokine/chemokine (CK/CCK) levels were measured before IA-E at baseline, after IA-E, and as long as there were adequate amounts of SF for knee aspiration (post). Characterization of synovial mononuclear cell infiltration and synovial vessels was carried out in 8 out of 14 knees by staining serial sections of synovial tissue biopsies for CD45, CD3, CD68, CD31 and CD105.

Results

At baseline, CRP and/or ESR were significantly correlated with SF-CK (interleukin- (IL-)1β, IL-1Ra, IL-6, IL-8) and CCK (CCL3). Post-IA injections, there was a decrease in SE in the knees in which aspiration following IA-E injection was possible as well as a significant reduction in SF WBC/μl and in SF-CK (IL-1β, IL-1Ra, IL-6 and IL-22). Pre- and post-IA-E injections, there were significant correlations between ST markers and SF-CK (IL-1β with CD45; IL-1β and IL-6 with CD31) and between SF-CCK (CCL4 and CCL3 with CD3). At the end of the study, there was a significant reduction in disease activity indexes (CRP, DAS, RAI, THOMP, KJAI) as well as in the ST markers (CD45; CD3).

Conclusions

Synovial effusion regression is a reliable indicator of the response to IA TNF-α blockers in PsA patients as it is confirmed by the correlation between SF biomarkers to disease activity and synovial tissue inflammation.     

Reasons given by mothers for discontinuing breastfeeding in Iran

Background

We have previously shown that in Iran, only 28% of infants were exclusively breastfed at six months, despite a high prevalence of breastfeeding at two years of age. The primary aim of this study was to investigate the reasons women discontinued exclusive breastfeeding.

Method

This retrospective study was based on questionnaires and interviews with 63,071 mothers of infants up to 24?months of age, divided into two populations: infants younger than six months and six months or older. The data were collected in 2005?C2006 from all 30 provinces of Iran.

Results

Only 5.3% of infants less than six months of age stopped breastfeeding (mean age of 3.2?months); more commonly in urban than rural areas. The most frequently cited reasons mothers gave for discontinuing exclusive breastfeeding were physicians?? recommendation (54%) and insufficient breast milk (self-perceived or true, 28%). Breastfeeding was common after six months of age: only 11% of infants discontinued breastfeeding, at a mean of 13.8?months. The most common reason for discontinuation at this age was insufficient breast milk (self-perceived or true, 45%). Maternal illness or medication (10%), infant illness (6%), and return to work (3%) were uncommon causes. Use of a pacifier was correlated with breastfeeding discontinuation. Maternal age and education was not associated with duration of breastfeeding. Multivariate analysis showed that using a pacifier and formula or other bottle feeding increased the risk of early cessation of breastfeeding.

Conclusions

Physicians and other health professionals have an important role to play in encouraging and supporting mothers to maintain breastfeeding.     

Derivation and preliminary validation of an administrative claims-based algorithm for the effectiveness of medications for rheumatoid arthritis

Introduction

Administrative claims data have not commonly been used to study the clinical effectiveness of medications for rheumatoid arthritis (RA) because of the lack of a validated algorithm for this outcome. We created and tested a claims-based algorithm to serve as a proxy for the clinical effectiveness of RA medications.

Methods

We linked Veterans Health Administration (VHA) medical and pharmacy claims for RA patients participating in the longitudinal Department of Veterans Affairs (VA) RA registry (VARA). Among individuals for whom treatment with a new biologic agent or nonbiologic disease-modifying agent in rheumatic disease (DMARD) was being initiated and with registry follow-up at 1 year, VARA and administrative data were used to create a gold standard for the claims-based effectiveness algorithm. The gold standard outcome was low disease activity (LDA) (Disease Activity Score using 28 joint counts (DAS28) ≤ 3.2) or improvement in DAS28 by > 1.2 units at 12 ± 2 months, with high adherence to therapy. The claims-based effectiveness algorithm incorporated biologic dose escalation or switching, addition of new disease-modifying agents, increase in oral glucocorticoid use and dose as well as parenteral glucocorticoid injections.

Results

Among 1,397 patients, we identified 305 eligible biologic or DMARD treatment episodes in 269 unique individuals. The patients were primarily men (94%) with a mean (± SD) age of 62 ± 10 years. At 1 year, 27% of treatment episodes achieved the effectiveness gold standard. The performance characteristics of the effectiveness algorithm were as follows: positive predictive value, 76% (95% confidence interval (95% CI) = 71% to 81%); negative predictive value, 90% (95% CI = 88% to 92%); sensitivity, 72% (95% CI = 67% to 77%); and specificity, 91% (95% CI = 89% to 93%).

Conclusions

Administrative claims data may be useful in evaluating the effectiveness of medications for RA. Further validation of this effectiveness algorithm will be useful in assessing its generalizability and performance in other populations.     

Peroxisome proliferator-activated receptor γ agonist effect on rheumatoid arthritis: a randomized controlled trial

Introduction

Rheumatoid arthritis (RA), a chronic inflammatory disease, is associated with insulin resistance. Experimental evidence indicates that the relationship between insulin resistance and inflammation is bidirectional: Inflammation promotes insulin resistance, and insulin resistance promotes inflammation. Therefore, we examined the hypothesis that pioglitazone, a thiazolidinedione peroxisome proliferator-activated receptor γ agonist, would decrease inflammation and disease activity and improve insulin resistance in patients with RA.

Methods

In a single-center, randomized, double-blind, placebo-controlled crossover study patients with RA (N = 34) receiving stable therapy were randomized to also receive either pioglitazone 45 mg daily (n = 17) or matching placebo (n = 17) for eight weeks. This was followed by a four-week washout period and alternative treatment for eight weeks. Outcomes included change in Disease Activity Score in 28 joints (DAS28) score, individual components of the DAS28 score and homeostatic model assessment for insulin resistance (HOMA). Intention-to-treat analysis and linear mixed-effects models were used.

Results

Patients had a mean (±SD) age of 51 (±14.2) years, 82.4% were female and baseline DAS28 high-sensitivity C-reactive protein (DAS28-CRP) was 4.58 (±1.1) units. Addition of pioglitazone was associated with a 9.3% reduction (95% confidence interval (CI) = 0.17% to 17.6%) in DAS28-CRP (P = 0.046), but no significant change in DAS28 erythrocyte sedimentation rate (DAS28-ESR) (P = 0.92). There was a 10.7mm (95% CI = 0.4 to 20.9 mm) improvement in patient-reported global health (P = 0.042), a 48.6% decrease (95% CI = 27.6% to 63.5%) in CRP (P < 0.001) and a 26.4% decrease (95% CI = 3.7% to 43.8%) in insulin resistance as measured by HOMA (P = 0.025), but no significant reduction in swollen or tender joint count or in ESR (all P > 0.05). Lower-extremity edema was more common during pioglitazone treatment (16%) than placebo (0%).

Conclusion

Addition of pioglitazone to RA therapy improves insulin resistance and modestly reduces RA disease activity measured by DAS28-CRP and two of its components, including patient-reported global health and CRP, but not DAS28-ESR or ESR.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT00763139","term_id":"NCT00763139"}}NCT00763139     

Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease

Background

Type 2 diabetes (T2D) is strongly associated with cardiovascular risk and requires medications that improve glycemic control and other cardiovascular risk factors. The authors aimed to assess the relative effectiveness of pioglitazone (Pio), metformin (Met) and any sulfonylurea (SU) combinations in non-insulin-treated T2D patients who were failing previous hypoglycemic therapy.

Methods

Over a 1-year period, two multicenter, open-labeled, controlled, 1-year, prospective, observational studies evaluated patients with T2D (n = 4585) from routine clinical practice in Spain and Greece with the same protocol. Patients were eligible if they had been prescribed Pio + SU, Pio + Met or SU + Met serving as a control cohort, once they had failed with previous therapy. Anthropometric measurements, lipid and glycemic profiles, blood pressure, and the proportions of patients at microvascular and macrovascular risk were assessed.

Results

All study treatment combinations rendered progressive 6-month and 12-month lipid, glycemic, and blood pressure improvements. Pio combinations, especially Pio + Met, were associated with increases in HDL-cholesterol and decreases in triglycerides and in the atherogenic index of plasma. The proportion of patients at high risk decreased after 12 months in all study cohorts. Minor weight changes (gain or loss) and no treatment-related fractures occurred during the study. The safety profile was good and proved similar among treatments, except for more hypoglycemic episodes in patients receiving SU and for the occurrence of edema in patients using Pio combinations. Serious cardiovascular events were rarely reported.

Conclusions

In patients with T2D failing prior hypoglycemic therapies, Pio combinations with SU or Met (especially Pio + Met) improved blood lipid and glycemic profiles, decreasing the proportion of patients with a high microvascular or macrovascular risk. The combination of Pio with SU or Met may therefore be recommended for T2D second-line therapy in the routine clinical practice, particularly in patients with dyslipidemia.     

Interleukin-23 is critical for full-blown expression of a non-autoimmune destructive arthritis and regulates interleukin-17A and RORγt in γδ T cells

Introduction

A protein analysis using a mass spectrometry indicated that there are serum proteins showing significant quantitative changes after the administration of infliximab. Among them, connective tissue growth factor (CTGF) seems to be related to the pathogenesis of rheumatoid arthritis (RA). Therefore, this study was conducted to investigate how CTGF is associated with the disease progression of RA.

Methods

Serum samples were collected from RA patients in active or inactive disease stages, and before or after treatments with infliximab. CTGF production was evaluated by ELISA, RT-PCR, indirect immunofluorescence microscopy, and immunoblotting. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase (TRAP) staining, a bone resorption assay and osteoclasts specific catalytic enzymes productions.

Results

The serum concentrations of CTGF in RA were greater than in normal healthy controls and disease controls. Interestingly, those were significantly higher in active RA patients compared to inactive RA patients. Furthermore, the CTGF levels significantly were decreased by infliximab concomitant with the disease amelioration. In addition, tumour necrosis factor (TNF)α can induce the CTGF production from synovial fibroblasts even though TNFα can oppositely inhibit the production of CTGF from chondrocytes. CTGF promoted the induction of the quantitative and qualitative activities of osteoclasts in combination with M-CSF and receptor activator of NF-κB ligand (RANKL). In addition, we newly found integrin αVβ3 on the osteoclasts as a CTGF receptor.

Conclusions

These results indicate that aberrant CTGF production induced by TNFα plays a central role for the abnormal osteoclastic activation in RA patients. Restoration of aberrant CTGF production may contribute to the inhibition of articular destruction in infliximab treatment.     

Low Dose Infliximab for Prevention of Postoperative Recurrence of Crohn’s Disease: Long Term Follow-Up and Impact of Infliximab Trough Levels and Antibodies to Infliximab

Objective

In patients with postoperative recurrence of Crohn’s disease endoscopic and clinical remission can be maintained for up to 1 year with low infliximab doses (3 mg/Kg). However, in theory low-dose infliximab treated patients could develop subtherapeutic trough levels, infiximab antibodies, and might loose response to therapy. To verify this hypothesis infliximab pharmacokinetics and clinical/endoscopic response were checked in a group of patients treated in the long term with low infliximab doses.

Design

Infliximab antibodies, infliximab levels, highly-sensitive CRP and fecal calprotectin were measured during the 8-week interval in 5 consecutive patients in clinical (Crohn’s Disease Activity Index < 150) and endoscopic (Rutgeerts scores 0–1) remission after one year of therapy with infliximab 3 mg/Kg. For comparison with reported standards, infliximab pharmacokinetics and inflammatory parameters were also tested in 6 Crohn’s disease patients who did not undergo surgery and who were in clinical remission while on infliximab 5 mg/Kg. Patients on low infliximab dose also underwent colonoscopy after 18 additional months of therapy.

Results

Highly sensitive CRP and fecal calprotectin increased in all patients during the 8-week interval. Infliximab trough levels were lower in patients treated with the low dose compared to controls (mean±SE: 2.0±0.3 vs 4.75±0.83 μg/mL respectively p<0.05). Infliximab antibodies were present in two of the subjects treated with low infliximab dose and in none of the controls. However, in low dose-treated patients after 18 additional months of therapy endoscopy continued to show mucosal remission and none of them developed clinical recurrence or side effects.

Conclusions

Patients treated with low infliximab doses had lower trough levels compared to patients treated with 5 mg/Kg and some developed antibodies to infliximab. However, low infliximab doses sustained clinical and endoscopic remission for a total of 30 months of treatment.     

Reversibility of stress-echo induced ST-segment depression by long-term oral n-3 PUFA supplementation in subjects with chest pain syndrome, normal wall motion at stress-echo and normal coronary angiogram

Background

Normal coronary arteries may coexist with abnormal coronary and systemic endothelial function in patients with chest pain. Recent work by the renowned Pisa echo-group elegantly suggests that isolated ST-segment depression during stress-echo (SE) can be used as a marker of coronary endothelial dysfunction, in the absence of stress-inducible wall motion abnormalities and in the absence of angiographically-significant coronary artery disease (CAD). The long chain n-3 polyunsaturated fatty acids (PUFAs) have been reported to possess several properties that may positively influence vascular function. The present study's hypothesis is that a 4 month-course of oral supplementation with n-3 PUFAs can reverse endothelial dysfunction.

Methods

Subjects were selected on the basis of the following criteria: 1) reported chest pain syndrome, 2) significant ST-segment depression during an otherwise normal SE, 3) absence of angiographically-significant CAD. Subjects underwent a 4-month course of oral supplementation with commercially available n-3 PUFA, 1 g once a day. Normalization of endothelial dysfunction was defined, at the end of the supplementation period, by the absence of significant ST-segment depression during repeat SE. We tested the aforementioned hypothesis in a very small series of consecutive subjects, with the intent to produce a hypothesis-generating study.

Results

Seven out of the total nine subjects enrolled (77.8%) had normal ST-segment during repeat SE performed after the 4 month course of therapy.

Conclusions

A striking rate of reversion of SE-induced ST-segment depression after oral n-3 PUFAs suggests reversion of coronary endothelial dysfunction; nonetheless these data need to be validated in larger, placebo-controlled studies.     

Characterization and sequence prediction of structural variations in α-helix

Background

Centralised resources such as GenBank and UniProt are perfect examples of the major international efforts that have been made to integrate and share biological information. However, additional data that adds value to these resources needs a simple and rapid route to public access. The Distributed Annotation System (DAS) provides an adequate environment to integrate genomic and proteomic information from multiple sources, making this information accessible to the community. DAS offers a way to distribute and access information but it does not provide domain experts with the mechanisms to participate in the curation process of the available biological entities and their annotations.

Results

We designed and developed a Collaborative Annotation System for proteins called DAS Writeback. DAS writeback is a protocol extension of DAS to provide the functionalities of adding, editing and deleting annotations. We implemented this new specification as extensions of both a DAS server and a DAS client. The architecture was designed with the involvement of the DAS community and it was improved after performing usability experiments emulating a real annotation task.

Conclusions

We demonstrate that DAS Writeback is effective, usable and will provide the appropriate environment for the creation and evolution of community protein annotation.