Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial

\ua9 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Background: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. Methods: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013–003413–18). Findings: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92\ub78% (SE 2\ub76) in the abatacept group and 69\ub72% (4\ub77) in the placebo group. Kaplan–Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0\ub7044). The difference in restricted mean survival time between groups was 53 days (95% CI 28–78; p<0\ub70001) at 12 months and 99 days (95% CI 38–161; p=0\ub70016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. Interpretation: Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. Funding: Bristol Myers Squibb

Seed germination ecology of echinochloa glabrescens and its implication for management in rice (Oryza sativa L.)

Echinochloa glabrescens is a C grass weed that is very competitive with rice when left uncontrolled. The competitive ability of weeds is intensified in direct-seeded rice production systems. A better understanding is needed of factors affecting weed seed germination, which can be used as a component of integrated weed management in direct-seeded rice. This study was conducted to determine the effects of temperature, light, salt and osmotic stress, burial depth, crop residue, time and depth of flooding, and herbicide application on the emergence, survival, and growth of two populations [Nueva Ecija (NE) and Los Baños (IR)] of E. glabrescens. Seeds from both populations germinated at all temperatures. The NE population had a higher germination rate (88%) from light stimulation than did the IR population (34%). The salt concentration and osmotic potential required to inhibit 50% of germination were 313 mM and -0.24 MPa, respectively, for the NE population and 254 mM and 20.33 MPa, respectively, for the IR population. Emergence in the NE population was totally inhibited at 4-cm burial depth in the soil, whereas that of the IR population was inhibited at 8 cm. Compared with zero residue, the addition of 5 t ha of rice residue reduced emergence in the NE and IR populations by 38% and 9%, respectively. Early flooding (within 2 days after sowing) at 2-cm depth reduced shoot growth by 50% compared with non-flooded conditions. Pretilachlor applied at 0.075 kg ai ha followed by shallow flooding (2-cm depth) reduced seedling emergence by 94-96% compared with the nontreated flooded treatment. Application of postemergence herbicides at 4-leaf stage provided 852100% control in both populations. Results suggest that integration of different strategies may enable sustainable management of this weed and of weeds with similar germination responses

Seed germination ecology of Echinochloa glabrescens and its implication for management in rice (Oryza sativa)

Echinochloa glabrescens is a C4 grass weed that is very competitive with rice when left uncontrolled. The competitive ability of weeds is intensified in direct-seeded rice production systems. A better understanding is needed of factors affecting weed seed germination, which can be used as a component of integrated weed management in direct-seeded rice. This study was conducted to determine the effects of temperature, light, salt and osmotic stress, burial depth, crop residue, time and depth of flooding, and herbicide application on the emergence, survival, and growth of two populations [Nueva Ecija (NE) and Los Banos (IR)] of E. glabrescens. Seeds from both populations germinated at all temperatures. The NE population had a higher germination rate (88%) from light stimulation than did the IR population (34%). The salt concentration and osmotic potential required to inhibit 50% of germination were 313 mM and -0.24 MPa, respectively, for the NE population and 254 mM and -0.33 MPa, respectively, for the IR population. Emergence in the NE population was totally inhibited at 4-cm burial depth in the soil, whereas that of the IR population was inhibited at 8 cm. Compared with zero residue, the addition of 5 t ha-1 of rice residue reduced emergence in the NE and IR populations by 38% and 9%, respectively. Early flooding (within 2 days after sowing) at 2-cm depth reduced shoot growth by 50% compared with non-flooded conditions. Pretilachlor applied at 0.075 kg ai ha-1 followed by shallow flooding (2-cm depth) reduced seedling emergence by 94 to 96% compared with the nontreated flooded treatment. Application of postemergence herbicides at 4-leaf stage provided 85 to 100% control in both populations. Results suggest that integration of different strategies may enable sustainable management of this weed and of weeds with similar germination responses

Activation of the cholinergic antiinflammatory reflex by occipitoatlantal decompression and transcutaneous auricular vagus nerve stimulation

Abstract Context The parasympathetic-mediated inflammatory reflex inhibits excessive proinflammatory cytokine production. Noninvasive techniques, including occipitoatlantal decompression (OA-D) and transcutaneous auricular vagus nerve stimulation (taVNS), have been demonstrated to increase parasympathetic tone. Objectives To test the hypothesis that OA-D and taVNS increase parasympathetic nervous system activity and inhibit proinflammatory cytokine mobilization and/or production. Methods Healthy adult participants were randomized to receive OA-D (5 min of OA-D followed by 10 min of rest; n=8), taVNS (15 min; n=9), or no intervention (15 min, time control; n=10) on three consecutive days. Before and after these interventions, saliva samples were collected for determination of the cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor α (TNF-α). Arterial blood pressure and the electrocardiogram were recorded for a 30-min baseline, throughout the intervention, and during a 30-min recovery period to derive heart rate and blood pressure variability markers as indices of vagal and sympathetic control. Results OA-D and taVNS increased root mean square of successive RR interval differences (RMSSD) and high frequency heart rate variability, which are established markers for parasympathetic modulation of cardiac function. In all three groups, the experimental protocol was associated with a significant increase in salivary cytokine concentrations. However, the increase in IL-1β was significantly less in the taVNS group (+66 ± 13 pg/mL; p&lt;0.05) than in the time control group (+142 ± 24 pg/mL). A similar trend was observed in the taVNS group for TNF-α (+1.7 ± 0.3 pg/mL vs. 4.1 ± 1.3 pg/mL; p&lt;0.10). In the OA-D group baseline IL-6, IL-8, and TNF-α levels on the third study day were significantly lower than on the first study day (IL-6: 2.3 ± 0.4 vs. 3.2 ± 0.6 pg/mL, p&lt;0.05; IL-8: 190 ± 61 vs. 483 ± 125 pg/mL, p &lt;0.05; TNF-α: 1.2 ± 0.3 vs. 2.3 ± 0.4 pg/mL, p&lt;0.05). OA-D decreased mean blood pressure from the first (100 ± 8 mmHg) to the second (92 ± 6 mmHg; p&lt;0.05) and third (93 ± 8 mmHg; p&lt;0.05) study days and reduced low frequency spectral power of systolic blood pressure variability (19 ± 3 mmHg2 after OA-D vs. 28 ± 5 mmHg2 before OA-D; p&lt;0.05), a marker of sympathetic modulation of vascular tone. OA-D also increased baroreceptor-heart rate reflex sensitivity from the first (13.7 ± 3.0 ms/mmHg) to the second (18.4 ± 4.3 ms/mmHg; p&lt;0.05) and third (16.9 ± 4.2 ms/mmHg; p&lt;0.05) study days. Conclusions Both OA-D and taVNS elicited antiinflammatory responses that were associated with increases in heart rate variability-derived markers for parasympathetic function. These findings suggest that OA-D and taVNS activate the parasympathetic antiinflammatory reflex. Furthermore, an antihypertensive effect was observed with OA-D that may be mediated by reduced sympathetic modulation of vascular tone and/or increased baroreceptor reflex sensitivity. </jats:sec

OP0178 IMAGING NEOANGIOGENESIS IN RHEUMATOID ARTHRITIS (INIRA): WHOLE-BODY SYNOVIAL UPTAKE OF A 99MTC-LABELLED RGD PEPTIDE IS HIGHLY CORRELATED WITH POWER DOPPLER ULTRASOUND

Background:Power Doppler ultrasound (PDUS) is superior to clinical examination in detecting synovitis in patients with rheumatoid arthritis (RA). Although dynamic and cheap it is impractical to scan large numbers of joints in routine clinical settings. MRI, whilst sensitive for synovitis, is expensive and routine use is limited to targeted joints. Bone scintigraphy produces whole body images but due to limited specificity is not routinely used.99mTc-maraciclatide (Serac Healthcare) is a radiolabelled tracer which binds with high affinity to integrin αvβ3, a cell-adhesion molecule up-regulated on neoangiogenic blood vessels. It therefore has the potential to image synovial inflammation at the whole-body level. We previously showed in a pilot study that uptake was seen in the inflamed joints of five RA patients and that this correlated with PDUS. This study explores correlation with PDUS in a larger groups of patients with varied disease activity.Objectives:To determine the correlation between ultrasound and99mTc-maraciclatide imaging in patients with rheumatoid arthritis.Methods:50 patients with RA fulfilling ACR 2010 classification criteria were recruited. Patients underwent an ultrasound scan of 40 joints with grey scale (GS) and PD quantification. Each joint was scored on a scale of 0-3 for GS and PD with a total score calculated for each patient. Within 3 hours of the ultrasound patients were injected with 740 MBq of99mTc-maraciclatide. Using a gamma camera, whole body planar views and dedicated hand and foot views were taken 2 hours after injection (Figure 1). Acquisition time was 20 minutes for whole body and 20 minutes for hand and foot views.99mTc-maraciclatide images were scored as positive or negative uptake for each joint (binary score). A quantitative score was also calculated for each joint where there was uptake with this corrected for background uptake. Total binary and quantitative scores per patient were calculated.Ultrasound and99mTc-maraciclatide scores were tested for correlation with Pearson’s correlation coefficient (r). Interrater agreement for 2 scorers was calculated using kappa (ĸ) and concordance correlation coefficient (Pc).Results:Strong correlation was seen when total PDUS was compared to binary scores (r=0.92, r2=0.85) (Figure 2) and quantitative scores (r=0.85, r2=0.72). ĸ was 0.82 and 0.79 for binary and ultrasound scores respectively.Pcwas 0.82 for quantitative scores. p was &lt;0.0005 for all results.99mTc-maraciclatide uptake was also seen in inflamed tendons/tendon sheaths. The imaging procedure was well-tolerated. There were no tracer-related adverse events.Figure 1.99mTc-maraciclatide imaging with dedicated hand and foot viewsConclusion:99mTc-maraciclatide uptake was highly correlated with PDUS highlighting its potential as an alternative imaging modality.99mTc-based planar imaging has the unique capacity to image the whole body and hence the total synovial inflammatory load in a quick acquisition. The imaging equipment to perform these scans is already widely available in radiology departments. Interpretation of scans is also much simpler compared to US/MRI. It could therefore have a role in key decision-making points in pathways for diagnosis, treatment failure, and remission prior to dose tapering.Figure 2.Correlation between total power doppler and99mTc-maraciclatide binary scoresDisclosure of Interests:None declared</jats:sec