BackgroundTNF inhibitors have become an important part of healthcare worldwide for inflammatory diseases such as RA1. Many publications show that responding patients have higher Adalimumab (Ada) serum trough levels (ATL) than non-responders. These factors are influenced by age, weight, gender or pharmacokinetics, which in turn depend on immunogenicity. Concomitant use of immunomodulators such as methotrexate (MTX) reduces immunogenicity and enhances therapy benefits1,3.Increasing drug dosage in patients with less response is the standard practice, while lowering dosage is advisable in patients achieving remission. Many recent publications2 assess serum trough levels that reflect optimal response and which could be used as benchmark for guidance to implement the Therapeutic Drug Monitoring.ObjectivesTo establish an optimal Ada serum trough level (ATL) range in RA patients associated with good clinical response.MethodsA prospective observational study with 40 RA patients under Ada treatment recruited in the Rheumatology Unit of Universitary Hospital La Paz was conducted. Demographic data, ATL and clinical activity of patients treated with 40 mg/kg every other week from 4 months up to 12 years of treatment were collected. A total of 206 samples were analyzed [χ=5 (3–13) samples/patient]. Disease activity was assessed using the DAS28 index and clinical improvement with ΔDAS28. ATL were measured with a capture ELISA3 [correlation with Promonitor (Derio, Vizcaya, Spain) k=1, r=0.91; and with Sanquin (Amsterdam, The Netherlands) k=1, r=0.86] and statistical analysis were performed with GraphPadPrism 5.0 software.ResultsDemographic data of our cohort were: mean age (±SD) 56.75±16.06, with 82.5% of females and 45% of patients treated with concomitant MTX. Sixty-five and 72% of patients were RF and ACPA positive, respectively. ATL were similar in patients treated with concomitant MTX (χ=3.82±2.42 μg/ml) or Ada monotherapy (χ=3.54±2.43 μg/ml) p=0.81.Consistent with previous studies1,2, low-disease activity patients (DAS28≤3.2) presented higher Ada circulating levels than patients with high-disease activity [3.7 μg/ml (IQR 2.97–5.48) vs. 1.71 μg/ml (IQR 0.23–4.51), p=0.01]. The median of Ada levels excluding the values (n=6) that showed immunogenicity was 3.42 μg/ml (IQR 1.55–5.03) where 3.50 μg/ml represented the most frequent value (15% of patients). Lack of clinical improvement (ΔDAS<1.2) was linked to drug levels below percentile 25 (p=0.04) whilst Ada levels above percentile 75 did not ensure more clinical improvement (p=0.7) than the values around the median.ConclusionsATL correlate with the disease activity and with the clinical improvement. The optimal range associated with good therapeutic response after the standard dose is 1.5–5 μg/ml. Higher circulating drug levels do not entail better response, which indicates they could be unnecessary. The knowledge of the optimal drug ranges can guide the Personalized Drug Therapy in order to maximise effectiveness and minimise costs.References Pouw, M.F., et al. ARD, 2013.Chen...
BackgroundBiologic therapy has been a major change in Rheumatoid Arthritis (RA) prognosis, but around 40% of patients (pts) fail to respond. Part of this treatment failure can be explained by the development of anti-drug antibodies (ADA), but the ADA-associated secondary inefficacies rate is currently unclearObjectivesTo assess in our AR cohort treated with Adalimumab (Ada), Infliximab (Ifx), etanercept (Etn), certolizumab (Czp), Tocilizumab (Tcz) and Abatacept (Abt) as 1st biologic agent, the frequency of drug suspension as well as the main causes for discontinuation and the secondary inefficacy rate associated with the development of immunogenicityMethodsFrom the RA cohort that initiated their 1st biologic agent at Hospital La Paz between 2005 and 2016, only those who had suspended those drugs were included, and causes for suspension were collected. Clinical activity was measured by DAS28 and Delta-DAS28 at 6 months of treatment to classify discontinuation by primary or secondary inefficacy. Drug levels (DL) and/or ADA were also measured by ELISA at 6 months since initiating the biologic agent in 43 pts and at drug discontinuation in 59 pts. Primary inefficacy was defined as DAS28>3.2 and delta-DAS28 <1.2 at 6 months with DL present. Secondary inefficacy was defined both as DAS28>3.2 plus delta-DAS28 <1.2 at 6 months with ADA+ and Delta-DAS28>1.2 or DAS28 <3.2 at 6 months with subsequent loss of efficacy. Statistical analysis was performed using SPSS version 20.0ResultsFrom the 246 pts who started their first biologic therapy, 144 (58%) pts who had definitively discontinued were included. [Ifx (n 35, 24%), Ada (n 40, 28%), Etn (n 30, 21%), Czp (n 23, 16%), Tcz (n 10, 7%) y Abt (n 6, 4%)]. 116 (80,6%) were women. The mean age was 56.3±14.7 years. The mean time of biologic was 2.23±1.96 years. From the global cohort, 18 (12.5%) drop out the treatment due to primary inefficacy, 41 (28.5%) to secondary inefficacy, 57 (39.6%) to adverse effects (AE), 11 (7.6%) to remission and 17 (11.8%) to other causes (surgery, pregnancy, etc.). 12.5% pts who discontinued due to AE or other causes had also a primary or secondary inefficacy; by including those pts in these last causes for suspension, a total of 20 pts (14%) failed due to primary inefficacy and 57 pts (39.6%) to secondary inefficacy. The most frequent AEs were: infections (35%), cutaneous AEs (psoriasis, rash, etc. (10.5%), infusion reactions (9%) and neoplasia (9%). Of the 59 pts who had DL/ADA measured at drug discontinuation, 42.4% were ADA +. Within the group that failed due to secondary inefficacy and had DL/ADA determined, 50% were ADA+; nevertheless this rate was smaller in suspensions due to other causes. Likewise, in the ADA+ pts, 73% suspended due to secondary inefficacyConclusionsIn our RA cohort, adverse effects were the main cause for discontinuation, with infections at 1st place. The 2nd cause conditioning interruption was the secondary inefficacy, in which 50% of our pts were ADA+ at drug discontinuation. These data suggest that the development of ADA ...
BackgroundThe term spondyloarthritis (SpA) encompass a group of crhonic inflammatory disease with predominant axial involvement. Anti-TNF therapy (AT) has stirred up the management of these diseases. Nevertheles, according to nationwide registries of the drug continuation rate in several countries, the rate of treatment failure is considerable. Nowdays there are insufficient data to evaluate the differences between responders (Resp-AT) and non-responders (Nonresp-AT) to anti-TNF therapy.ObjectivesTo compare the main sociodemographic, clinical and analytical features at baseline, after 6 months of treatment and at the end of the first anti-TNF therapy of responders to a first anti-TNF therapy and non-responders to several anti-TNF therapies form our cohort of patients diagnosed with SpA. We also analized the association between drug levels (DL) and antidrug antibody (ADA) in non-responders to several anti-TNF.Methods181 patients were included, 155 (85%) kept receiving their first AT therapy (responders) and 26 (15%) had discontinued at least two different AT therapies. The main demographic features, disease activity (BASDAI, ASDAS, CRP and ESR) were measured at baseline, after 6 months (v-6) and when the first AT was discontinued. Serum drug levels and/or ADA were measured at drug discontinuation of anti-TNF treatment and last visit in non-responders and responders respectively.ResultsThe mean age was 55.3±15 and 50±10.8 in the resp-AT and nonresp-AT groups, respectively. The demographic and clinical characteristics of both groups are shown in Table 1. At baseline, a lower BMI was observed in the resp-AT group (25.6±5 resp-AT, 28.7±5 nonresp-AT, p=0.013); 59% and 35% were in concomitant treatment with DMARDS at baseline in the resp-AT and nonresp-AT groups respectively (p=0.032); 33% of the resp-AT were in monotherapy in the last visit compared to 62% of the nonresp-AT when discontinued the 1st AT (p=0.008). There were no differences in BASDAI (5.6±2 resp-AT, 6.1±1.9 nonresp-AT, p=0.2) and ASDAS (3.3±1.1 resp-AT, 3.4±1.1 nonresp-AT, p=0.8) at baseline. In v-6, the resp-AT group had a better clinical response in terms of BASDAI (3.2±2.3 in resp-AT, 4.7±2.4 in nonresp-AT, p=0.004) and ASDAS (1.7±0.9 in resp-AT, 2.7±1.2 in nonresp-AT, p=0.00), as well as in the delta-ASDAS (ΔASDAS) (1.56±1.2 resp -AT, 0.7±0.9 nonresp-AT, p=0.04). However, delta-BASDAI (ΔBASDAI) showed no difference between the two groups (2.3±2.3 resp-AT, 1.5±1.6 nonresp-AT, p=0.1). 24% of the nonresp-AT were ADA + at drug discontinuation, while only 0.7% of the AT-resp (AT) were ADA + (p=0.00) at last visit.ConclusionsIn our cohort of patients with axial SpA, a significant improvement in BASDAI, ASDAS and ΔASDAS after 6 months of treatment is associated with a lower frequency of drop-out of the first AT. Moreover a lower BMI, DMARDS at baseline and absence of ADA determine a better response to AT treatment.Disclosure of InterestNone declared
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