Background The aim of our study was to investigate the influence of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and body mass index (BMI) on circulating drug levels and clinical response to tumour necrosis factor inhibitor (TNFi) therapy in axial spondyloarthritis (axSpA) patients. Methods Prospective observational study during 1 year with 2 cohorts (Madrid and Amsterdam) including 180 axSpA patients treated with standard doses of infliximab or adalimumab. Patients were stratified by BMI, being 78 (43%) normal weight (18.5–24.9 kg/m 2 ) and 102 (57%) overweight/obese (≥ 25.0 kg/m 2 ). After the first year of treatment, TNFi trough levels were measured by capture ELISA. Clinical response to TNFi was defined as ∆BASDAI ≥ 2 and clinical remission as BASDAI < 2 and CRP ≤ 5 mg/L. Logistic regression models were employed to analyse the association between concomitant csDMARDs and BMI with drug levels and clinical response. Results Seventy-nine patients (44%) received concomitant csDMARDs. The administration of concomitant csDMARDs (OR 3.82; 95% CI 1.06–13.84) and being normal weight (OR 18.38; 95% CI 2.24–150.63) were independently associated with serum TNFi drug persistence. Additionally, the use of concomitant csDMARDs contributed positively to achieve clinical response (OR 7.86; 95% CI 2.39–25.78) and remission (OR 4.84; 95% CI 1.09–21.36) in overweight/obese patients, but no association was found for normal-weight patients (OR 1.10; 0.33–3.58). Conclusions The use of concomitant csDMARDs with TNFi may increase the probability of achieving clinical response in overweight/obese axSpA patients. Further research studies including larger cohorts of patients need to be done to confirm it. Electronic supplementary material The online version of this article (10.1186/s13075-019-1849-3) contains supplementary material, which is available to authorized users.
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...
BackgroundIn patients with axial spondyloarthritis (axSpA), the use of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate (MTX) and sulfasalazine (SSZ), as well as the body mass index (BMI) have been associated with circulating TNFi levels. Recently, BMI has also been associated with TNFi clinical response but csDMARDs have not shown any significant clinical improvement for axial manifestations1. However, no study has assessed in the same population the influence of both factors -csDMARDs and BMI- on drug serum levels and clinical responseObjectivesTo investigate the influence of csDMARD and BMI on circulating drug levels and clinical response to TNFi therapy in axSpA patientsMethodsA 1 year follow-up prospective observational study with two cohorts (Madrid and Amsterdam) including 180 axSpA patients treated with standard doses of infliximab (41%) or adalimumab (59%). Laboratory and clinical parameters were collected every 6 months. Patients were stratified by BMI: normal-weight (18.5–24.9 kg/m2) and overweight-obesity (>25.0 kg/m2). TNFi trough levels were measured by capture ELISA2. Clinical response to TNFi was defined as ▵BASDAI ≥2. The association between concomitant csDMARDs and BMI with drug levels and clinical response to TNFi at 1 year was analysed through multivariate log-regression models (odds ratio and 95% CI). The presence of significant interactions between covariates was tested and all models were adjusted for age, gender, HLA-B27, disease duration, TNFi-type (for drug levels) and baseline BASDAI and CRP (for clinical response)ResultsSeventy-nine out of 180 patients (44%) received concomitant csDMARDs (MTX 14%, SSZ 20% and MTX +SSZ 10%), 78 (43%) patients were normal-weight and 102 (57%) overweight-obese. Mean (SD) age and disease duration was 47(13) and 11(9) years respectively, 59% were males, 73% HLA-B27 +and 78% had r-axSpA. Concomitant csDMARDs (OR: 3.82; IC 95%: 1.06–13.84) and being overweight-obese (OR: 18.38; IC 95%: 2.24–150.63) were independently associated with serum TNFi drug presence. Furthermore, a significant interaction between csDMARDs and BMI with clinical response was found. While the use of concomitant csDMARD contributed positively to achieve clinical response in overweight-obese patients (OR: 7.86; IC 95%: 2.39–25.78), no association was found for normal-weight patients (OR: 1.10; 0.33–3.58). Additionally, sensitivity analysis using remission status and ASDAS were performed and showed results along the same lineConclusionsIn patients with axSpA, TNFi drug persistence is positively influenced by the use of concomitant csDMARDs and especially by being normal-weight. However, TNFi clinical response is associated with the use of concomitant csDMARDs only in overweight-obese, but not in normal-weight patients. Based on this, the use of concomitant csDMARDs in patients with axSpA could be beneficial in overweight patientsReferences[1] van der Heijde D, et al. Ann Rheum Dis. 2017;76(6):978–991.[2] Pascual- Salcedo D, et al. Rheumatology (O...
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