Association of HLA-DRB1 alleles with clinical responses to the anti-interleukin-17A monoclonal antibody secukinumab in active rheumatoid arthritis.

OBJECTIVE: To assess whether preliminary findings of associations between the HLA-DRB1*04 and HLA-DRB1* shared epitope (SE) allelic groups and response to the anti-IL-17A mAb secukinumab in RA were reproducible in an independent RA cohort. METHODS: Biologic-naïve subjects (n = 100) with RA by 2010 criteria with tender/swollen joint counts (each ≥6) and high-sensitivity CRP (hsCRP) >10 mg/l were randomized 2:1 to secukinumab 10 mg/kg i.v. or placebo every 2 weeks until week 10. Potential associations with treatment response to secukinumab at week 12 (DAS28-CRP change from baseline by analysis of covariance, ACR20 response rate by logistic regression) were assessed for HLA-DRB1*04 (primary end point), HLA-DRB1*SE and HLA-DRB1 position 11 V/L (HLA-DRB1*pos11 V/L) allelic groups, and baseline levels of hsCRP, RF and anti-CCP. RESULTS: Secukinumab was significantly more effective than placebo in reducing DAS28-CRP (-2.41 vs -0.71; P < 0.0001) and producing ACR20 responses (87.1% vs 25.0%; P < 0.0001) at week 12. The HLA-DRB1*04 allelic group was not significantly related to secukinumab response vs placebo. For change from baseline in DAS28-CRP, HLA-DRB1*SE (P = 0.003) and HLA-DRB1*pos11 V/L (P = 0.002) allelic groups were associated with positive treatment response. Higher RF levels, but not anti-CCP positivity, were significantly associated with DAS28-CRP reductions (P = 0.015) and ACR20 (P = 0.008) responses. Secukinumab was well tolerated. CONCLUSION: Secukinumab significantly reduced signs and symptoms of RA vs placebo. As the HLA-DRB1*SE and HLA-DRB1*pos11 V/L results were driven by lack of placebo response in carriers, the hypothesis of clinical utility for HLA-DRB1* allelic groups in RA anti-IL-17A short-term response prediction could not be corroborated. TRIAL REGISTRATION: ClinicalTrials.gov; https://clinicaltrials.gov/; NCT01426789.

Estimation of microbial methane generation and oxidation rates in the municipal solid waste landfill of Kaluga city, Russia.

Using a theoretical model and mass isotopic balance, biogas (methane and CO(2)) released from buried products at their microbial degradation was analysed in the landfill of municipal and non-toxic industrial solid organic waste near Kaluga city, Russia. The landfill contains about 1.34 x 10(6) tons of waste buried using a 'sandwich technique' (successive application of sand-clay and waste layers). The delta(13)C values of biogenic methane with respect to CO(2) were-56.8 (+/-2.5) per thousand, whereas the delta(13)C of CO(2) peaked at+9.12 per thousand (+1.4+/-2.3 per thousand on average), reflecting a virtual fractionation of carbon isotopes in the course of bacterial CO(2) reduction at the landfill body. After passing through the aerated soil layers, methane was partially oxidised and characterised by delta(13)C in the range of-50.6 to-38.2 per thousand, evidencing enrichment in (13)C, while the released carbon dioxide had delta(13)C of-23.3 to-4.04 per thousand, respectively. On the mass isotopic balance for the delta(13)C values, the methane production in the landfill anaerobic zone and the methane emitted through the aerated landfill surface to the atmosphere, the portion of methane oxidised by methanotrophic bacteria was calculated to be from 10 to 40% (averaged about 25%). According to the theoretical estimation and field measurements, the annual rate of methane production in the landfill reached about 2.9(+/-1.4)x10(9) g C CH(4) yr(-1) or 5.3(+/-2.6)x10(6) m(3) CH(4) yr(-1). The average rates of methane production in the landfill and methane emission from landfill to the atmosphere are estimated as about 53 (+/-26) g C CH(4) m(-2) d(-1) (or 4 (+/-2) mol CH(4) m(-2) d(-1)) and 33 (+/-12) g C CH(4) m(-2) d(-1) (or 2.7 (+/-1) mol CH(4) m(-2) d(-1)), respectively. The calculated part of methane consumed by methanotrophic bacteria in the aerated part of the landfill was 13(+/-7) g C CH(4) m(-2) d(-1) (or 1.1(+/-0.6) mol CH(4) m(-2) d(-1)) on average.