In order to compare the relative bioavailability of orally administered methotrexate (MTX) with i.m. administration in patients with rheumatoid arthritis, we compared the pharmacokinetics of MTX at both the usual starting dose of 7.5 mg and at higher established maintenance dosages in 21 patients. Pharmacokinetic measures were repeated approximately 6 and 18 months after baseline while patients consumed their usual maintenance doses of MTX (17.0 +/- 3.8 mg). The relative bioavailability of the usual maintenance dose of MTX was reduced by 13.5% compared with the initial dose of 7.5 mg (P = 0.026). Area under the serum concentration vs time curve (AUC) was significantly reduced with oral vs i.m. administration at usual maintenance doses (decrease of 0.729 mumol.h/l by oral administration, P = 0.027), but not at a 7.5 mg dose of MTX. Clinicians using MTX should not assume constant and complete bioavailability across the dose range used to treat patients with rheumatoid arthritis. Our observations explain the reported clinical success of switching from an oral to a parenteral route of administration in patients receiving maintenance doses of MTX.

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The presence of resident microbiota on and inside plants is hypothesized to influence many phenotypic attributes of the host. Likewise, host factors and microbe-microbe interactions are believed to influence microbial community assembly. Rigorous testing of these hypotheses necessitates the ability to grow plants in the absence or presence of resident or defined microbiota. To enable such experiments, we developed the scalable and inexpensive FlowPot growth platform. FlowPots have a sterile peat substrate amenable to colonization by microbiota, and the platform supports growth of the model plant Arabidopsis thaliana in the absence or presence of soil-derived microbial communities. Mechanically, the FlowPot system is unique in that it allows for total-saturation of the sterile substrate by "flushing" with water and/or nutrient solution via an irrigation port. The irrigation port also facilitates passive drainage of the substrate, preventing root anoxia. Materials to construct an individual FlowPot total ~$2.A simple experiment with 12 FlowPots requires ~4.5 h of labor following peat and seed sterilization. Plants are grown on FlowPots within a standard tissue culture microbox after inoculation, thus the Flowpot system is modular and does not require a sterile growth chamber. Here, we provide a detailed assembly and microbiota inoculation protocol for the FlowPot system. Collectively, this standardized suite of tools and colonization protocols empowers the plant microbiome research community to conduct harmonized experiments to elucidate the rules microbial community assembly, the impact of microbiota on host phenotypes, and mechanisms by which host factors influence the structure and function of plant microbiota.3

BackgroundOf patients with RA, ∼40% of do not achieve a minimal acceptable improvement (ACR20) despite modern biologic therapy.1,2,3 Granulocyte-macrophage colony-stimulating factor (GM–CSF) is implicated in RA pathogenesis via myeloid and granulocyte cell lineage activation. In a 12-week Phase IIa study, mavrilimumab, a first-in-class inhibitor of the GM–CSF receptor-α demonstrated a sustained effect via this novel therapeutic pathway in RA.4ObjectivesTo evaluate the efficacy and safety of mavrilimumab in patients with moderate to severe, adult-onset RA in a 24-week, Phase IIb study.MethodsPatients (18–80 yrs; inadequate response to ≥1 DMARDs; DAS28–CRP ≥3.2; ≥4 SJC) receiving MTX were randomized to receive 1 of 3 SC mavrilimumab dosages (150, 100, 30 mg every other week [eow]) or placebo (PBO) plus MTX (7.5–25.0 mg/week). Co-primary endpoints were change in DAS28–CRP (Day 1 to Week 12) and ACR20 response rate (Week 24). Safety and tolerability were measured through assessment of AEs and pulmonary parameters. Results were analyzed using the modified ITT population.Results326 patients from Europe, South America, and South Africa (mean [SD] age, 51.8 [11.1] yrs; female, 86.5%; mean [SD] DAS28–CRP, 5.8 [0.9]; RF+/anti-CCP+, 81.9%) received mavrilimumab 150, 100 or 30 mg eow or PBO (N=79, 85, 81 and 81, respectively). At Week 12, a statistically significant difference in DAS28–CRP change from baseline (p<0.001) was observed for all dosages of mavrilimumab vs. PBO. At Week 24, a significantly greater percentage of all mavrilimumab-treated patients also met the ACR20 co-primary endpoint vs. PBO (table). A dosage response was observed across several secondary endpoints, with separation from PBO evident as early as Week 1 and first dose. The most common treatment-emergent AEs were headache (7.6%, 4.7%, 6.2%, 2.5%), nasopharyngitis (7.6%, 3.5%, 4.9%, 7.4%) and bronchitis (5.1%, 1.2%, 3.7%, 7.4%) for mavrilimumab 150, 100, 30 mg eow or PBO, respectively. There was no increase in pulmonary AEs for mavrilimumab vs. PBO (6.3%, 3.5%, 6.2% vs. 9.9%). No serious infections were observed in the 100 and 150 mg eow groups. Two cases of pneumonia were observed (one each in mavrilimumab 30 mg eow and PBO groups). There were no deaths or anaphylaxis, and no apparent dosage relationship for AEs. >90% of patients entered a long-term, open-label extension study.ConclusionsThis Phase IIb study demonstrated the potential benefit of inhibiting macrophage activity via the GM–CSF receptor-α pathway on RA disease activity. The study met both co-primary endpoints with a clear dosage response. Mavrilimumb was well-tolerated over the 24-week study period.ReferencesWeinblatt ME, et al. N Engl J Med 1999;340:253–9.Lipsky PE, et al. N Engl J Med 2000;343:1594–602.Weinblatt ME, et al. Arthritis Rheum 2003;48:35–45,Burmester GR, et al. Ann Rheum Dis 2013;72:1445–52.AcknowledgementsFunded: MedImmune. Editorial assistance: N Panagiotaki, QXV Communications, UK†Joint senior authors.Disclosure of InterestG. Burmester Grant/research support from: AbbVie, P...

Background Despite the availability of multiple therapies for treatment of RA in the US, there exists a high rate of discontinuation/change of therapy. This may be attributed to multiple factors including: loss of efficacy, adverse effects, patient/physician preference, access and/or expectation bias. This study was designed to examine initiation of biologic therapies within the US CORRONA database and characterize reasons for their discontinuation. Methods In the CORRONA registry, patients meeting the following criteria during calendar years 2002-2011 were included: age >18; RA onset age >16 years; and ≥6 months follow-up after initiation of first or subsequent biologic therapy, defined as a visit ≥180 days after initiation of biologic therapy. Biologic agents included TNF inhibitors (TNFi’s) and non-TNFi‘s. Treatment discontinuation was defined as the first report of stopping initial therapy or initiation of a new biologic at/or between visits on a follow-up MD questionnaire. Up to 3 reasons for discontinuation were captured. Results 6209 patients (78.5% female; mean age 57.6±12.8, median RA duration 8 years; 43.4% biologic naïve, 26.1% CDAI >22) met inclusion criteria. 5010 (80.7%) were receiving TNFi’s and 1199 (19.3%) non-TNFi’s. Overall median time to discontinuation/change of therapy was 25.1 months: 82.2% remained on initiated treatment at 6 months and 67.3% at 1 year. Median time to discontinuation was 26.5 months in those receiving TNFi’s (n=5010) vs 20.5 months for non-TNFi’s (n=1199) [log rank p<0001]. Overall proportions of patients receiving TNFi’s vs non-TNFi’s remaining on treatment were 82.5%, 68.2% and 52.2% at 6, 12, and 24 months vs 80.9%, 63.4% and 46.0%, respectively. Of 3584 discontinuations, reasons were captured for 1763 including: loss of efficacy: 35.8%; safety: 20.1%; MD/patient preference: 27.8%/ 17.9% and access to treatment: 9.0%. In patients receiving TNFi’s: percentages were 34.2, 20.8, 27.5, 17.9 and 9.6% and non-TNFi’s: 44.2, 16.8, 29.1, 17.9 and 6.0% respectively. Those 5010 initiating TNFi’s had shorter RA duration, lower disease activity, mHAQ, pain and fatigue scores than 1199 initiating non-TNFi’s. Biologic naïve patients (n=2693) had slightly higher durability although not significant [log-rank p=0.0601]. In multivariate analyses, the strongest predictors of discontinuation were higher CDAI and mHAQ scores, patient report of anxiety/depression, and year of biologic initiation. Conclusions Patients in the US discontinue roughly 1/3rd of biologic therapies at 1 year, and 1/2 by 2 years. Rates and recorded reasons for treatment discontinuation were similar for both TNFi’s and non-TNFi biologics. Lack of efficacy was the single most common reason for discontinuation, although others reported were multifactorial and in part reflect expectations on the part of both patients and physicians. Disclosure of Interest V. Strand Consultant for: CORRONA, Inc., S. Williams Shareholder of: AstraZeneca, Employee of: AstraZeneca, P. Miller Shareholder of: AstraZeneca, Employee of: ...

BackgroundMethotrexate (MTX) is frequently administered in combination with biologics for the treatment of rheumatoid arthritis (RA). MTX may be subsequently discontinued due to intolerance or nonadherence, and/or to reduce medication burden once disease control is achieved. Previous studies have established the efficacy of tocilizumab (TCZ) initiated as monotherapy (MONO), but the impact of MTX withdrawal in patients achieving good clinical response to TCZ+MTX (COMBO) has not been evaluated.ObjectivesTo evaluate whether TCZ-MONO is non-inferior to TCZ-COMBO in maintaining clinical response in patients who achieve low disease activity with TCZ-COMBO.MethodsUS patients with RA who were inadequate responders to MTX were enrolled: initial combination therapy included MTX (15 mg/week orally) plus TCZ 162 mg subcutaneous (SC) either weekly (qw; for patients ≥100 kg) or every 2 weeks (q2w; for patients <100 kg). Dose escalation from q2w to qw was allowed at week 12 in patients who had not achieved low disease activity (DAS28 ≤3.2). If patients achieved DAS28-ESR ≤3.2 at week 24, they were randomized (double-blind) 1:1 to receive either TCZ-MONO or continue TCZ-COMBO until week 52. Patients who did not achieve DAS28 ≤3.2 were assigned to an open-label arm and continued TCZ-COMBO until week 52. The primary outcome measured was the comparison of mean change in DAS28-ESR score in the randomized cohort between weeks 24 and 40, between the TCZ-MONO or TCZ-COMBO arms (noninferiority margin of 0.6). Secondary outcomes included the proportion of patients achieving DAS28 <2.6, DAS28 ≤3.2 and American College of Rheumatology 20%/50%/70% (ACR20/50/70) responses at weeks 40 and 52, and safety. Trial registration number: NCT01855789.ResultsOf 718 patients enrolled, 296 were randomized at week 24 (TCZ-MONO, n=148; TCZ-COMBO, n=148). Early discontinuation in the randomized cohort occurred in 12.2% of patients in the TCZ-MONO group and 10.2% in the TCZ-COMBO group. Baseline characteristics were balanced between treatment groups (mean age 55.5 years; 74.8% female; mean RA duration 6.8 years; mean DAS28-ESR 6.3). At week 24, DAS28 scores were similar in both groups, but ACR responses were ∼8–11% lower in the TCZ-MONO group prior to MTX withdrawal (randomization). The mean change in DAS28 was similar between the randomized treatment groups (Table 1). For the primary efficacy analysis, the mean changes in DAS28 from week 24 to week 40 were 0.46 and 0.14 in the TCZ-MONO and TCZ-COMBO groups, respectively (95% CI: 0.045–0.592). This study met the primary endpoint by demonstrating that discontinuing MTX in TCZ responders was noninferior to continuing MTX. The safety of TCZ-SC in this study was consistent with the known safety profile with no new safety signals observed (Table 2). The most common SAE was infection, occurring in 4.1% of patients. TCZ-COMBO had greater frequency of AEs, SAEs and serious infections than TCZ-MONO.ConclusionsThese results demonstrate that patients receiving TCZ-COMBO who achieve low disease activity can discontinue ...

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BackgroundIt is unclear whether anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) status are predictive of response to rheumatoid arthritis (RA) therapy.ObjectivesTo assess whether baseline anti-CCP/RF status is associated with treatment response in patients with RA initiating abatacept (ABA) or a tumour necrosis factor-alpha inhibitor (TNFi).MethodsPatients who initiated ABA or a TNFi within the Corrona RA registry between June 2002 and January 2015 were eligible if they had: anti-CCP and RF testing at or prior to initiation; a follow-up visit 6 months after initiation (±3 months); and Clinical Disease Activity Index (CDAI) measured at or within 4–6 months prior to initiation and after 6 months' treatment. Seropositivity was identified for anti-CCP (≥20 U/mL) and RF (≥40 U/mL). At 6 months, the primary outcome was ΔCDAI, with secondary outcomes being achievement of remission (CDAI ≤2.8 in those with low, moderate or high baseline disease activity) and low disease activity (LDA; CDAI ≤10 in those with moderate or high baseline disease activity). Unadjusted and adjusted linear and logistic regression analyses were performed by baseline anti-CCP/RF status: double positive (anti-CCP+/RF+), single positive (anti-CCP+/RF– or anti-CCP–/RF+) and double negative (anti-CCP–/RF–). Adjusted models controlled for baseline age, sex, BMI, CDAI score, co-morbidity index and number of prior biologic DMARDs.Results566 patients starting ABA (244 double positive; 167 single positive; 155 double negative) and 1715 starting a TNFi (774 double positive; 470 single positive; 471 double negative) were identified. Most patients were female (ABA: 79–83%; TNFi: 74–80%) and middle-aged (mean age 57–58 years in ABA, 54–57 years in TNFi), with established disease (mean disease duration 9–11 years in ABA, 6–8 years in TNFi) and moderate disease activity (mean CDAI 18–23 in ABA, 18–19 in TNFi). For patients who initiated ABA, double positive status was associated with a significantly greater response compared with double negative status on all outcomes (ΔCDAI −8.9 vs −4.5, p=0.002; LDA 43% vs 26%, p=0.002; remission 15% vs 5%, p=0.001). Additionally, single positive status was associated with a greater likelihood of remission as compared with double negative status for ABA users (12% vs 5%, p=0.018). Conversely, there were no significant differences in responses between anti-CCP/RF groups in the TNFi users (double positive vs double negative: ΔCDAI −7.5 vs −6.8, p=0.46; LDA 39% vs 35%, p=0.20; remission 16% vs 14%, p=0.38). In adjusted models, there are significant differences in the outcomes based on anti-CCP/RF status among ABA users but not TNFi users (Figure).ConclusionsThese real-world data demonstrate that baseline anti-CCP+/RF+ is associated with better clinical response to ABA, with the strongest association observed for double seropositivity. In contrast, no relationship was evident between anti-CCP/RF status and response to a TNFi, suggesting that the predictive value of autoantibodies is dependent on drug mechani...