Effectiveness and safety of subcutaneous abatacept in biologic-naïve RA patients at Week 52: A Japanese multicentre investigational study (ORIGAMI study).

OBJECTIVES: To evaluate the effectiveness and safety of abatacept over 52 weeks in biologic-naïve rheumatoid arthritis (RA) patients with moderate disease activity in the prospective, 5-year, observational study (ORIGAMI study) in Japan. METHODS: Abatacept (125 mg) was administered subcutaneously once a week. Clinical outcomes included Simplified Disease Activity Index (SDAI) remission at Week 52 (primary endpoint), Japanese Health Assessment Questionnaire (J-HAQ), EuroQol 5-Dimension Questionnaire (EQ-5D), treatment retention, and safety. The results were compared with those of conventional synthetic disease-modifying antirheumatic drug (csDMARD) controls from the ongoing Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry. RESULTS: Overall, 325 patients were enrolled, with a mean age of 66.9 ± 12.7 years. The proportion of patients achieving SDAI remission (≤3.3) at Week 52 was 18.9% (95% CI: 14.3-23.6) and low disease activity (≤11) was 53.3% (95% CI: 47.4-59.1). A significant improvement was observed in J-HAQ and EQ-5D over 52 weeks in both the abatacept and csDMARD groups. The probability of abatacept treatment retention at Week 52 was 69.9% (95% CI: 64.7-75.5). Adverse events and serious adverse events were reported in 50.0% and 12.1% of patients, respectively. CONCLUSIONS: Abatacept significantly improved disease activity, physical disability, and quality of life for up to 52 weeks in RA patients in a real-world setting.

Disease activity early in treatment as a predictor of future low disease activity in RA patients treated with iguratimod.

OBJECTIVES: This retrospective observational study aimed to examine the efficacy of iguratimod with and without concomitant methotrexate (MTX) and to estimate the adequate observational period for predicting low disease activity (LDA) achievement at 24 weeks in patients with rheumatoid arthritis (RA). METHODS: All patients treated with iguratimod were registered in a Japanese multicenter registry. Multivariate analyses were performed to identify predictive factors for LDA achievement at 24 weeks. Receiver operating characteristic (ROC) curve analyses were performed to estimate the association of 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) at each time point with achievement of LDA at 24 weeks and determine a cut-off for DAS28-ESR. RESULTS: A total of 123 patients were treated with iguratimod with (n = 65) or without (n = 58) MTX. Iguratimod therapy resulted in significant clinical improvement in both groups. Multivariate analysis revealed that DAS28-ESR at each time point was an independent significant predictor of LDA achievement at 24 weeks. Cut-off values of DAS28-ESR at 12 weeks based on ROC curves were 3.2 and 3.6 in patients with and without MTX, respectively. CONCLUSIONS: Iguratimod was effective in RA patients in clinical practice. Our results suggest that 12 weeks may be a sufficient period to judge the medium-term efficacy of iguratimod in patients treated with and without MTX.

Concomitant methotrexate and tacrolimus augment the clinical response to abatacept in patients with rheumatoid arthritis with a prior history of biological DMARD use.

This observational retrospective study examined whether abatacept efficacy could be augmented with concomitant methotrexate (MTX) or tacrolimus (TAC) in patients with rheumatoid arthritis (RA) who experienced failure with prior biological disease-modifying antirheumatic drugs (DMARDs) and in whom favorable therapeutic efficacy is difficult to achieve. All patients with a prior biological DMARD history who were treated with abatacept for 52 weeks and registered in a Japanese multicentre registry were included. Clinical efficacy and safety of abatacept according to the concomitant drug used, i.e., none (ABT-mono), MTX (ABT-MTX), and TAC (ABT-TAC), were compared. A greater mean percent change of DAS28-ESR was observed in the ABT-TAC group compared with the ABT-mono group at weeks 12 (-20.5 vs. -5.4 %, p = 0.035) and 24 (-25.0 vs. -11.0 %, p = 0.036). ABT-MTX and ABT-TAC groups had a significantly higher proportion of patients who achieved low disease activity (LDA) within 52 weeks compared with the respective baselines, while no significant change was observed in the ABT-mono group. A higher proportion of patients in the ABT-TAC group achieved EULAR moderate response compared with the ABT-mono group at week 52 (66.7 vs. 35.0 %, p = 0.025). Multivariate logistic regression analysis revealed that concomitant TAC use was independently associated with the achievement of LDA and EULAR response at 52 weeks, while concomitant MTX use was not. Concomitant TAC use may offer a suitable option for RA patients treated with abatacept after prior biological DMARD failure, likely because both abatacept and TAC affect T cell activation.

Drug retention rates of second biologic agents after switching from tumor necrosis factor inhibitors for rheumatoid arthritis in Japanese patients on low-dose methotrexate or without methotrexate.

OBJECTIVES: The purpose of this study was to explore drug retention rates of second biologic agents after switching from tumor necrosis factor inhibitors (TNFi) in clinical practice in patients with rheumatoid arthritis (RA) on low-dose methotrexate (MTX) or without MTX. METHODS: A total of 169 RA patients who had been withdrawn from first-course TNFi therapy and received a different TNFi or tocilizumab (TCZ) as a second biologic agent were selected from the Tsurumai Biologics Communication Registry, an observational cohort database. Retention rates of second biologic treatment were compared by the type of first TNFi and second biologic agents. RESULTS: Eighty-six patients received first-course infliximab (IFX) or adalimumab (ADA) therapy, and 83 patients received first-course etanercept (ETN) therapy. The former group had a significantly higher retention rate (IFX, 81.1%; ADA, 83.3%) of the second biologic therapy compared to the latter (56.6%, p < 0.001, log-rank test). Drug retention rates of the second biologic agent after switching from IFX/ADA were significantly higher with ETN (90.0%) and TCZ (94.7%) than with ADA/IFX (59.3%). Drug retention rates of the second biologic agent after switching from ETN were significantly higher with TCZ (75.9%) than with ADA/IFX (46.3%). The differences were significant even after adjusting for baseline clinical variables using the Cox proportional hazards model. CONCLUSIONS: Drug retention rates of IFX and ADA after switching from the first TNFi were significantly lower compared to those of ETN and TCZ in patients on low-dose MTX or without MTX.

Design and evaluation of locked nucleic acid-based splice-switching oligonucleotides in vitro.

Antisense-mediated modulation of pre-mRNA splicing is an attractive therapeutic strategy for genetic diseases. Currently, there are few examples of modulation of pre-mRNA splicing using locked nucleic acid (LNA) antisense oligonucleotides, and, in particular, no systematic study has addressed the optimal design of LNA-based splice-switching oligonucleotides (LNA SSOs). Here, we designed a series of LNA SSOs complementary to the human dystrophin exon 58 sequence and evaluated their ability to induce exon skipping in vitro using reverse transcription-polymerase chain reaction. We demonstrated that the number of LNAs in the SSO sequence and the melting temperature of the SSOs play important roles in inducing exon skipping and seem to be key factors for designing efficient LNA SSOs. LNA SSO length was an important determinant of activity: a 13-mer with six LNA modifications had the highest efficacy, and a 7-mer was the minimal length required to induce exon skipping. Evaluation of exon skipping activity using mismatched LNA/DNA mixmers revealed that 9-mer LNA SSO allowed a better mismatch discrimination. LNA SSOs also induced exon skipping of endogenous human dystrophin in primary human skeletal muscle cells. Taken together, our findings indicate that LNA SSOs are powerful tools for modulating pre-mRNA splicing.

Clinical results for tocilizumab over one year in the clinical setting as assessed by CDAI (clinical disease activity index): CRP at week 12 and MMP-3 at week 24 are predictive factors for CDAI.

To investigate the clinical results of 1 year tocilizumab (TCZ) treatment of rheumatoid arthritis patients in clinical practice by using the clinical disease activity index (CDAI). Thirty-one patients with inadequate response to DMARDs, including methotrexate (MTX), or TNF inhibitors received TCZ (8 mg every 4 weeks). The clinical responses were measured using the 28-joint disease activity score (DAS28-ESR) and CDAI. Matrix metalloproteinase-3 (MMP-3) was assessed as a serological biomarker. Mean baseline DAS28-ESR was 5.96, decreasing to 2.89 at week 52 with a remission rate (DAS28-ESR < 2.6) of 35.5%. Mean baseline CDAI was 28.4, decreasing to 10.2 at week 52 with a remission rate (CDAI ≤ 2.8) of 22.6%. Of patients whose CRP levels had fallen to below the limit of detection by week 12, 65.2% achieved remission or low disease activity as assessed by CDAI at week 52. Median baseline MMP-3 level was 165.7 ng/mL, decreasing to 79.5 ng/mL at week 52. A positive correlation was seen between CDAI at week 52 and MMP-3 level from week 12 onward. About 50% of the patients treated with TCZ in clinical practice achieved a low disease activity level at week 52 as assessed by CDAI, which does not include acute-phase proteins. Our results suggested that CRP levels falling to below the limit of detection by week 12 and MMP-3 ≤ 80.6 ng/mL at week 24 could predict low disease activity or remission at week 52 as assessed by CDAI.

Contribution of fulvic acid to the photochemical formation of Fe(II) in acidic Suwannee River fulvic acid solutions.

We investigated the contribution of fulvic acid to the photoformation of Fe(II) using aqueous Suwannee River fulvic acid (SRFA) as a surrogate for the humic-like substances (HULIS) found in atmospheric condensed phases. The effects of pH (3.2, 4.1, and 5.0) and wavelength (313, 334, 366, and 405nm) on Fe(II) photoformation were studied using monochromatic radiation at 20 degrees C. We calculated the wavelength-dependent Fe(II) photoformation efficiency values ("E-value"), defined here as a weighted sum of the product of the quantum yield and molar absorptivity of each Fe(II)-forming chemical species, and found that the E-values of acidic SRFA solutions were similar to those of Fe(OH)(2+). In addition, a comparison showed that the acidic SRFA solutions did not form Fe(II) fast enough to account for the observed Fe(II) formation efficiencies of the aqueous extracts of authentic aerosol samples. It was observed that 17-73% of Fe(III) had been reduced to Fe(II) in the dark in acidic SRFA solutions with added Fe(III) ranging from 0.5 to 10muM. The results of this study suggest that HULIS is unlikely to be the major reducing ligand in the process of photochemical formation of Fe(II) in acidic atmospheric drops. However, HULIS could reduce Fe(III) to Fe(II) in the dark, which in turn, could be important for night-time ()OH formation via the reaction between Fe(II) and H(2)O(2) (the Fenton reaction).