The presence of low ADA trough levels without AAA is strongly predictive of clinical response in 67% of cases after ADA optimization. Conversely, low ADA levels with detectable AAA are associated with ADA failure, and switching to IFX should be considered. ADA trough levels >4.9 μg/ml are associated with failure of two anti-TNF agents (ADA and IFX) in 90% of cases, and switching to another drug class should be considered.
The presence of AAA is associated with a higher risk of loss of clinical response to adalimumab, whereas high TRA is associated with greater clinical response rates in CD. More data are needed in ulcerative colitis.
The automated NOVA View(®) reading of slides allows saving time, and an improvement in the standardization. Nevertheless, it requires a confirmation by a qualified operator, to interpret mixed patterns in particular.
This review discusses the rationale behind recommending immunopharmacological guidance of long-term therapies with anti-TNF-α specific biotherapies. "Arguments why therapeutic decision-making should not rely on clinical outcomes alone are presented. Central to this is that the use of theranostics (i.e., monitoring circulating levels of functional anti-TNF-α drugs and antidrug antibodies) would markedly improve treatment because therapies can be tailored to individual patients and provide more effective and economical long-term clinical benefits while minimising risk of side effects. Large-scale immunopharmacological knowledge of the pharmacokinetics of TNF-α biopharmaceuticals in individual patients would also help industry to develop more effective and safer TNF-α inhibitors" [1].
BackgroundSince biologic therapy development, rheumatoid arthritis (RA) prognosis improves dramatically. Tumor necrosis factor alpha (TNF) is a proinflammatory cytokine that plays an important role in RA pathogenesis. Infliximab (IFX, Remicade®), is a human-murine chimerical monoclonal IgG antibody targeting TNF, approved for RA after inadequate response to conventional synthetic disease modifying antirheumatic drugs (csDMARDs).Clinical improvement is heterogeneous with primary or secondary therapy failure. Furthermore, no factors to predict response are available in the daily practice. Detection of antibody towards IFX (ATI) was described early in the development of this drug. The hypothesis is that ATI reduce IFX concentration associated with a lack of efficacy.ObjectivesTo evaluate methotrexate effects on tumor necrosis factor alpha (TNF) bioactivity and antibody against infliximab (ATI) development in rheumatoid arthritis (RA) patients treated by infliximab (IFX).MethodsIn a longitudinal multicenter study including 39 RA patients requiring IFX therapy, clinical data and blood sample were recorded at the inclusion (W0), at the 6th week (W6), at the 6th month (W22) and at the 12th month (W54) of treatment.ResultsIFX trough level increased from W0 to W54 and distribution became heterogeneous at W22 at the time of first ATI detection. From W22, an inverse correlation between IFX trough level and ATI concentrations was observed (p<0.05). ATI concentrations inversely correlated with EULAR response at W22 (p<0.005). TNF bioactivity decreased from W0 to W6, and distribution was heterogeneous from W22. TNF bioactivity correlated with both DAS28 (p<0.05) and ATI concentrations (p<0.001) at W22. Methotrexate therapy was associated with absence of ATI at W22 (p<0.05), and TNF bioactivity was lower than in patients with other synthetic disease modifying antirheumatic drugs (p<0.005).ConclusionsThis suggests that methotrexate plays a key role on TNF bioactivity and against ATI developmentDisclosure of InterestNone declared
BackgroundThe goal of rheumatoid arthritis (RA) strategy is to reach remission or at least a low disease activity. When this gaol is reached, no clear guideline exist to manage therapy. Recently, STRASS (Spacing TNF-blocker injections in RA Study) provided evidence of step-down therapeutic strategy with adalimumab or etanercept (1).ObjectivesWe investigated if drug dosages and their antidrug antibodies (ADAb) could predict relapse during the 18 months of STRASS study.MethodsWe assessed 131 serum among the 137 included in STRASS study (60 and 71 for adalimumab and etanercept, respectively). Serum were collected at the time of randomisation. Adalimumab and etanercept blood concentrations and theirs ADAb were assessed by ELISA (Theradiag, Marne-La-Vallee, France). For this study, relapse was defined as DAS28>2.6 with DAS28 increase >0.6 since the previous study visit.ResultsCharacteristics of the 131 patients similar to 137 from the initial STRASS study (data not shown). The median age was 54.5 [48.3–61.8] years. One hundred and two (77%) were female. The median disease duration was 6.5 [4.5–12.4] years. The median DAS28, ESR, and CRP were 2.0 [1.5–2.3], 10 [6–17], and 3 [2–4]mg/mL, respectively. Methotrexate was the main DMARDs used (n=91; 70%). No baseline characteristics were associated with relapse during tapering or not. In patients treated with etanercept, etanercept level was similar in case of relapse or not. Similarly, adalimumab level was comparable in case of relapse or not. However, in patients treated with adalimumab, ADABs was significantly higher in case of relapse compared to no relapse (0.94±0.27 ng/ml vs. 0.27±0.76 ng/ml; P=0.03, respectively). However, this difference was not clinically pertinent.ConclusionsNo difference was observed in adalimumab or etanercept blood level to predict relapse in RA patients with low disease activity. However, a slight increased of ADAb for adalimumab was observed. Its signification needs further investigation.ReferencesFautrel B, Pham T, Alfaiate T, et al. Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study). Annals of the Rheumatic Diseases 2016; 75: 59–67.AcknowledgementAbbVie provided funding for this study. Analysis was performed independently to AbbVie.Disclosure of InterestNone declared
Background The infliximab (IFX) is a monoclonal chimeric antibody targeting the Tumor Necrosis Factor alpha (TNFα), indicated in the rheumatoid arthritis (RA) treatment. Only two-third of RA patients respond to anti-TNFα therapy. At this time, predictive factors of response to anti-TNFα are missing. Commercial kit for IFX and antibody toward IFX (ATI) detection in the serum is now available Objectives We assessed the development of ATI during one year of IFX treatment in RA patients treated. We also assessed IFX concentrations during the treatment and investigated correlations between the clinical response and IFX concentration and/or ATI development Methods In a longitudinal multicentric study including 40 RA patients requiring IFX therapy, we assessed the TNFα, IFX, and ATI serum concentrations at various time points: before treatment (W0), at the 6th week (W6), at the 6th month (W22) and at the 12th month (W54) of treatment. All blood samples were collected just before the infliximab infusion. The mean age was 54.2±13.28 years old, the RA mean duration was 11.4±7.8 years, the initial DAS 28 was 5.31±0.86. The clinical response was evaluated according to the EULAR criteria. Clinical response was good in 32% and 24% at W22 and W54, respectively; moderate in 47% and 48% at W22 and W 54, respectively; and bad in 21 and 28% at W22 and W54, respectively. Concentrations were determined by a commercial ELISA (LisaTracker, BMD, France). The data were analyzed with Kruskall-Wallis test (ANOVA), then by a multiple comparison Dunnett post-hoc and with a significance threshold P<0.05. The non parametric correlations were made with Spearman test. Results The ATI development (concentration upper than 10 μg/ml) was observed early from W6 in 7% of patients but with a low concentrations (lower than 20 μg/ml). However, at W22 and W54, ATI were respectively detected in 45% and 46% of patients. The IFX concentrations increased in time (P<0.001). Initially, median was 0.04 μg/ml, then 4.3 μg/ml at W6 (P<0.05), then decreased at W22 (0.63 μg/ml, P<0.01) and at W54 (1.08 μg/ml, P<0.01). We found no correlation between the TNFα concentration and the RA activity assessed by the DAS 28. The initial median serum TNFα concentration was 7.2 pg/ml, increased at W6 to 7.2 pg/ml, and remained high relative at W22 and W54 (P<0.05). At W22 and W54, we observed detection in the serum detection of IFX or ATI. We did not observe presence of both. At W22 and W54, the ATI distribution was heterogeneous in terms of clinical response (P<0.05) with a higher concentration among non-responders than in responders (P<0.05). At 6 months, the ATI presence in serum increased the risk by two to discontinue IFX treatment. ATI development was not correlated with taking a DMARD or dose methotrexate, or corticosteroids prescription. Conclusions Our study shows an heterogeneity in the ATI development at W22 and W54. However, IFX concentrations were homogenous at W6 and heterogeneous from W22 to W54. This suggests that ATI development contribute to IFX heterogene...
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