High BMI is associated with lower TNF-α inhibitor serum trough levels and higher disease activity in patients with axial spondyloarthritis.

BACKGROUND: TNF-α inhibitor (TNFi) serum trough levels have previously been found to be related to disease activity in axial spondyloarthritis (axSpA). However, most research regarding serum trough levels has been conducted in patients who only recently started TNFi therapy. Therefore, our objective was to explore TNFi serum trough level measurements in relation to disease activity and BMI in the total axSpA population in daily clinical practice, also including patients on long-term TNFi therapy. METHODS: Consecutive patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort were approached for a TNFi serum trough level measurement during their regular outpatient visit at the UMCG. Spearman's correlation coefficient was used to analyse the relation of serum trough levels with disease activity and BMI. Logistic regression was performed to analyse the relation between therapeutic drug levels and disease activity, corrected for potential confounders, including BMI. RESULTS: Thirty-four patients on adalimumab and 21 patients on etanercept were included. Mean age was 45 ± 12 years, 47% were male, median BMI was 26.4 (IQR 23.9-32.5) and median treatment duration was 41 months (range 2-126). According to definitions of Sanquin, 47% of patients had therapeutic serum trough levels. No significant correlations were found between TNFi levels and disease activity (ASDAS-CRP: adalimumab: ρ = -0.16, p = 0.39; etanercept: ρ = -0.29, p = 0.20). TNFi levels were moderately correlated with BMI (adalimumab: ρ = -0.48, p = 0.004; etanercept: ρ = -0.50, p = 0.021). Patients with active disease (ASDAS ≥ 2.1) showed higher BMI than patients with inactive disease (median 29.7 vs. 24.6, p = 0.015). In multivariable regression analyses, BMI was identified as the only confounder for the relationship between therapeutic drug levels and ASDAS. CONCLUSION: In this cross-sectional, observational study of axSpA patients mainly on long-term treatment with TNFi, higher BMI was significantly associated with lower adalimumab and etanercept serum trough levels and higher disease activity.

Analysing cord blood levels of TNF inhibitors to validate the EULAR points to consider for TNF inhibitor use during pregnancy.

BACKGROUND: To minimise placental transfer of tumour necrosis factor inhibitors (TNFi), the European League Against Rheumatism (EULAR) created points to consider (PtC) for the use of TNFi during pregnancy. We are the first to validate the EULAR-PtC by analysing TNFi concentrations in cord blood. METHODS: Patients were derived from the Preconceptional Counselling in Active Rheumatoid Arthritis Study. TNFi was stopped at the time points recommended by the EULAR. Maternal blood and cord blood were collected and analysed for the concentration of TNFi. RESULTS: 111 patients were eligible for the analysis. Median stop time points were gestational age (GA) 37.0 weeks for certolizumab pegol, GA 25.0 weeks for etanercept, GA 19.0 weeks for adalimumab and GA 18.4 weeks for infliximab. Certolizumab pegol (n=68) was detectable in 5.9% of cord blood samples, with a median concentration of 0.3 µg/mL (IQR: 0.2-1.3) and a median cord/maternal concentration ratio of 0.010. Etanercept (n=30) was not detected in any cord blood samples. Adalimumab (n=25) was detectable in 48.0% of cord blood samples, with a median concentration of 0.5 µg/mL (IQR: 0.2-0.7) and a median concentration ratio of 0.062 (IQR: 0.018-0.15). Infliximab (n=14) was detectable in 57.1% of cord blood samples, with a median concentration of 0.4 µg/mL (IQR: 0.1-1.2) and a median concentration ratio of 0.012 (IQR: 0.006-0.081). CONCLUSION: Compliance with the EULAR-PtC results in absence or low levels of TNFi in cord blood.

An optimized method for plasma extracellular vesicles isolation to exclude the copresence of biological drugs and plasma proteins which impairs their biological characterization.

Extracellular vesicles (EVs) are cell membrane-derived phospholipid bilayer nanostructures that contain bioactive proteins, enzymes, lipids and polymers of nucleotides. They play a role in intercellular communication and are present in body fluids. EVs can be isolated by methods like ultracentrifugation (UC), polyethylene-glycol-precipitation (PEG) or size exclusion chromatography (SEC). The co-presence of immunoglobulins (Ig) in EV samples isolated from plasma (pEVs) is often reported and this may influence the assessment of the biological function and phenotype of EVs in bio- and immunoassay. Here, we studied the presence of an Ig-based therapeutic (etanercept) in pEV samples isolated from rheumatoid arthritis (RA) patients and improved the isolation method to obtain purer pEVs. From plasma of etanercept (Tumor-necrosis-factor (TNF)-α antibodies)-treated RA patients pEVs were isolated by either UC, PEG or SEC. SEC isolated pEVs showed the highest particle-to-protein ratio. Strong TNF-α inhibition determined in a TNF-α sensitive reporter assay was observed by pEVs isolated by UC and PEG, and to a lesser extent by SEC, suggesting the presence of functional etanercept. SEC isolation of etanercept or labelled immunoglobulin G (IgG) showed co-isolation of these antibodies in the pEV fraction in the presence of plasma or a high protein (albumin) concentration. To minimize the presence of etanercept or immunoglobulins, we extended SEC (eSEC) column length from 56mm to 222mm (total stacking volume unchanged). No effect on the amount of isolated pEVs was observed while protein and IgG content were markedly reduced (90%). Next, from six etanercept- treated RA patients, pEVs were isolated on a eSEC or standard SEC column, in parallel. TNF-α inhibition was again observed in pEVs isolated by conventional SEC but not by eSEC. To confirm the purer pEVs isolated by eSEC the basal IL-8 promoter activation in human monocytes was determined and in 4 out of 5 SEC isolated pEVs activation was observed while eSEC isolated pEVs did not. This study shows that extended SEC columns yielded pEVs without detectable biologicals and with low protein and IgG levels. This isolation method will improve the characterization of pEVs as potential biomarkers and mediators of disease.

Serum drug concentrations to optimize switching from adalimumab to etanercept in rheumatoid arthritis.

Objectives: Inadequate response to adalimumab can be caused by insufficient blockade of the target tumour necrosis factor (TNF) at low serum concentrations. In such cases, patients may respond to another TNF inhibitor. We investigated whether the serum adalimumab concentration is related to the efficacy of a second TNF inhibitor, etanercept, in rheumatoid arthritis (RA). Methods: Patients with RA starting etanercept treatment were prospectively observed in the Reade Rheumatology Registry. In patients previously on adalimumab, serum concentrations were determined before treatment discontinuation. According to this concentration, three subgroups were formed: < 0.5 µg/mL, 0.5-5.0 µg/mL, and ≥ 5.0 µg/mL. The European League Against Rheumatism (EULAR) good/moderate response rate after 52 weeks of etanercept was compared between the switcher subgroups and biologic-naive patients. Results: In total, 449 consecutive patients were included, of whom 69 switched from adalimumab (15%) and 380 were biologic naive (85%). EULAR good or moderate response was achieved by 74% of the biologic-naive patients and by 72%, 50%, and 52% of switchers with adalimumab concentration < 0.5 µg/mL, 0.5-5.0 µg/mL, and ≥ 5.0 µg/mL, respectively (p = 0.15). Patients with an adalimumab concentration ≥ 0.5 µg/mL were significantly less likely to achieve EULAR good/moderate response on etanercept compared to biologic-naive patients, whereas patients with a concentration < 0.5 µg/mL did not significantly differ from patients starting etanercept without prior biologic treatment. Conclusion: RA patients with an inadequate response to adalimumab, in the presence of sufficient drug concentrations, benefit less from switching to another TNF inhibitor, etanercept.

Effective serum level of etanercept biosimilar and effect of antidrug antibodies on drug levels and clinical efficacy in Chinese patients with ankylosing spondylitis.

OBJECTIVES: To investigate the effective serum level of etanercept biosimilar in Chinese patients with ankylosing spondylitis (AS) who achieve AS Disease Activity Score-C-reactive protein (ASDAS-CRP) < 2.1, and the effect of antidrug antibodies on drug levels and clinical efficacy. METHODS: Our study enrolled 60 patients with AS who were treated with etanercept biosimilar. Serum and clinical data were collected at baseline and treatment weeks 4, 12, and 24. Drug levels and antidrug antibody levels were measured using an enzyme-linked immunosorbent assay while tumour necrosis factor (TNF)-α levels were measured using cytometric bead array. A receiver operating characteristic (ROC) curve was used to analyse effective serum level of etanercept biosimilar. RESULTS: Patients with ASDAS-CRP ≥ 2.1 exhibited significantly lower drug levels than those with ASDAS-CRP < 2.1 did. The cut-off values of effective serum level of patients with AS who achieved ASDAS-CRP < 2.1 at weeks 4, 12, and 24 were 2.32, 2.12, and 2.36 µg/mL, respectively. Patients with drug levels above the cut-off value had lower Bath AS Disease Activity Index (BASDAI) and TNF-α levels. Antidrug antibodies had no effect on the Assessment of Spondylosis Arthritis International Society (ASAS) remission rates, but patients with antidrug antibodies had lower drug levels and higher TNF-α levels. CONCLUSIONS: Detecting serum drug levels and antidrug antibody levels might facilitate estimation of the clinical efficacy and adjustment of medication regimen during etanercept biosimilar therapy in Chinese patients with AS.

Etanercept concentration and immunogenicity do not influence the response to Etanercept in patients with juvenile idiopathic arthritis.

OBJECTIVE: To investigate the relationship of clinical response of Juvenile Idiopathic Arthritis (JIA) to etanercept (ETN) with ETN levels, and the presence of anti-drug antibodies to ETN (ADAb). METHODS: Prospective study of JIA patients under 18 years old. Clinical and pharmacological data were collected at two visits. JIA clinical inactivity and activity were assessed according to the Wallace criteria and to the Juvenile Arthritis Disease Activity Score (JADAS). ETN and ADAb serum levels assessments were determined using ELISA-based assays. RESULTS: 126 patients were enrolled. The median duration of ETN treatment at inclusion was 569 days (range 53-2340). ADAb were undetectable (<10 ng/ml) in 171/218 (78%) samples and were > 25 ng/mL in 2/218 samples. No significant relationship between ETN concentration and the clinical inactivity status and JIA activity was found using either univariate logistic regression or multiple logistic regression analysis, adjusted on one individual descriptors, time since diagnosis, time of sampling, use of corticosteroids or methotrexate and classification of JIA. No correlation was found between the remission status and the detection of ADAb. CONCLUSION: This study did not demonstrate any correlation between JIA activity and circulating ETN levels in a large population of patients with JIA previously treated with ETN for at least 1.5 months. As described for adults, our study confirms that ETN is marginally immunogenic in pediatric patients. These results do not support the clinical usefulness of a monitoring of ADAb or ETN concentrations for the management of this group of JIA patients if they fail to achieve clinical inactive disease.

Adherence to etanercept therapy in rheumatoid arthritis patients during 3 years of follow-up.

OBJECTIVES: To determine the percentage non-adherence to etanercept in patients with rheumatoid arthritis during three years of follow-up. METHODS: During study visits in this prospective cohort study, blood samples were taken to determine serum etanercept concentrations using ELISA and patients were asked if they had missed an etanercept dose, at which date and for what reason. Non-adherence was defined as serum etanercept concentration <0.1 µg/mL and no valid reason to miss the prescribed etanercept dose. RESULTS: In total, 292 consecutive patients treated with etanercept were included. Most patients had a valid reason to miss their etanercept dose (25/37). In total 12 out of 292 patients (4.1%, 95% confidence interval 2.2-7.2) were non-adherent during the 3 year period. In a small percentage of patients (3.4%, 95% confidence interval 0.8-10.4) who failed to respond to etanercept therapy, according to their rheumatologist, this was associated with inadequate exposure to etanercept and thus non-adherence. CONCLUSION: In this study, adherence to etanercept therapy was measured using serum etanercept concentration. In most patients an absent etanercept concentration was due to a medical reason. Furthermore, the majority of patients were adherent to etanercept therapy and had adequate drug exposure. In total, only 12 out of 292 patients (4.1%) were non-adherent during 3 years of follow-up. These findings highlight that only a small minority of patients are non-adherent to etanercept treatment, especially compared to adherence rates of other drugs. However, physicians should be aware that in patients failing to respond to treatment, non-adherence is a possible cause.

Application of nSMOL coupled with LC-MS bioanalysis for monitoring the Fc-fusion biopharmaceuticals Etanercept and Abatacept in human serum.

The principle of nano-surface and molecular-orientation limited (nSMOL) proteolysis has a unique characteristic Fab-selective proteolysis for antibody bioanalysis that is independent of a variety of monoclonal antibodies by the binding antibody Fc via Protein A/G in a pore with 100 nm diameter and modified trypsin immobilization on the surface of nanoparticles with 200 nm diameter. Since minimizing peptide complexity and protease contamination while maintaining antibody sequence specificity enables a rapid and broad development of optimized methods for liquid chromatography-mass spectrometry (LC-MS) bioanalysis, the application of regulatory LC-MS for monitoring antibody biopharmaceuticals is expected. nSMOL is theoretically anticipated to be applicable for representative Fc-fusion biopharmaceuticals, because Protein A/G-binding site Fc exists on the C-terminus, and its functional domain is available to orient and interact with the reaction solution. In this report, we describe the validated LC-MS bioanalysis for monitoring Ethanercept and Abatacept using nSMOL technology. The quantitation range of Ethanercept in human serum was from 0.195 to 100 µg/mL using the signature peptide VFCTK (aa.43-47), and that of Abatacept was from 0.391 to 100 µg/mL using the signature peptide MHVAQPAVVLASSR (aa.1-14). Both proteins fulfilled the guideline criteria for low-molecular-weight drug compounds. The results indicate that the clinical and therapeutic monitoring for antibody and Fc-fusion biopharmaceuticals are adequately applicable using nSMOL proteolysis coupled with LC-MS bioanalysis.

Tumour necrosis factor-α/etanercept complexes in serum predict long-term efficacy of etanercept treatment in seronegative rheumatoid arthritis.

OBJECTIVE: To study whether serum levels of tumour necrosis factor-α (TNF-α), free or bound to etanercept, in biological-naïve adults with rheumatoid arthritis (RA) could predict the long-term efficacy of etanercept, measured as drug survival. METHOD: We identified 145 biological-naïve patients with RA starting treatment with etanercept at the Department of Rheumatology, Skåne University Hospital (1999-2008), of whom 16 had seronegative and 129 seropositive RA. TNF-α in serum was quantified using enzyme-linked immunosorbent assay in samples from the onset of treatment and at 6 week follow-up. Drug survival time was used to evaluate the long-term efficacy of etanercept. RESULTS: Levels of TNF-α were significantly increased at follow-up compared to at the start. At the 6 week follow-up, circulating TNF-α mainly comprised TNF-α in complex with etanercept. Longer drug survival time correlated with increased TNF-α at 6 week follow-up in the patients with seronegative RA, but not in the seropositive patients. CONCLUSION: We demonstrated that levels of circulating TNF-α increased in almost all individuals after initiation of treatment with etanercept and that this increase mainly comprised TNF-α in complex with etanercept. More importantly, this increase may predict drug survival in adults with seronegative, but not seropositive, RA and suggests that measuring TNF-α/etanercept complexes in serum may be relevant in patients with seronegative RA.

Intrapatient Variability in the Pharmacokinetics of Etanercept Maintenance Treatment.

AIM: Etanercept has shown to mediate a favorable effect on immune-mediated inflammatory diseases (IMID), including plaque psoriasis. Therapeutic drug monitoring (TDM) of etanercept could improve clinical outcome and cost-effectiveness. A high intrapatient variability (IPV) of etanercept trough concentrations at standard dosing would reduce the feasibility of therapeutic drug monitoring. Studies have focused on the interpatient differences associated with the exposure to biologics. The aim of this study was to determine IPV of etanercept and correlate etanercept trough concentrations and IPV with treatment response. METHODS: Repetitive serum samples of 29 psoriasis patients on standard etanercept maintenance treatment were collected. In these samples, etanercept trough concentrations were determined and IPV was assessed in relation to response to treatment. RESULTS: The median IPV of etanercept trough concentrations was 33.7% (Q1 = 21.3% and Q3 = 51.7%) ranging from 8% to 155%. All 6 nonresponders showed an IPV at or above the median value of 33.7%. The 6 nonresponders showed a higher IPV as compared to the 23 responders (53.9% versus 24.2%; P = 0.031). The mean etanercept trough concentration for each patient ranged from 0.7 to 6.8 mcg/mL, with a median trough concentration of 2.7 mcg/mL. Patients with an IPV above the median had lower mean etanercept trough concentrations compared to patients with an IPV below the median (1.96 mcg/mL, 95% CI, 1.7-2.4 versus 3.2 mcg/mL, 95% CI, 2.7-4.0; P = 0.001). CONCLUSIONS: The median IPV of etanercept trough concentrations in this study population was 33.7%. A higher IPV was correlated with lower etanercept trough concentrations and with nonresponsiveness. Prospective trials are required to demonstrate the value of adjusting the etanercept dose based on drug trough concentrations. The relatively high IPV observed in this study may complicate therapeutic drug monitoring.

Prolongation of Biologic Dosing Intervals in Patients With Stable Psoriasis: A Feasibility Study.

BACKGROUND: Biologics are usually licensed according to the "one dose fits all" principle. It is therefore suspected that a significant number of patients with psoriasis are overtreated. However, evidence for successful dose reduction of biologics in psoriasis is scarce. The aim of this study was to investigate whether the dosing interval of 3 biologics, adalimumab, etanercept, or ustekinumab could be prolonged successfully in patients with plaque psoriasis. METHODS: In a prospective exploratory cohort study, 59 patients with psoriasis on maintenance treatment with adalimumab, etanercept, or ustekinumab were included. After a run-in period of 6 weeks, the dosing interval of the biologics was prolonged according to a predefined schedule. Our primary objective was to determine the proportion of patients who could maintain a successful prolongation of the per label dosing interval. Secondary objectives were to evaluate the predictive value of baseline serum trough concentrations for successful dosing interval prolongation and to explore the feasibility of dosing interval prolongations in off-label-treated patients. RESULTS: In the per label group, 7 out of 16 (44%) adalimumab patients, 5 out of 16 (31%) etanercept patients, and 2 out of 10 (20%) ustekinumab patients achieved a successful dosing interval prolongation. Baseline serum trough concentrations did not differ significantly between patients with successful dosing interval prolongation and failures. In the off-label group, prolongation in patients with already extended intervals was unsuccessful. For patients with shortened intervals, minor prolongation was successful in 3 out of 17 (17.6%) patients. CONCLUSIONS: Prolongation of the per label biologic dosing interval was feasible in approximately 30% of patients with psoriasis with stable minimal disease activity and can reduce costs in clinical practice. Baseline serum trough concentrations were not predictive for successful dosing interval prolongation.

LBEC0101, A Proposed Etanercept Biosimilar: Pharmacokinetics, Immunogenicity, and Tolerability Profiles Compared with a Reference Biologic Product in Healthy Male Subjects.

OBJECTIVES: We performed this study to compare the pharmacokinetic (PK), immunogenicity, and tolerability profiles of etanercept between LBEC0101, a proposed biosimilar, and Enbrel®, the reference biological product. METHODS: A randomized, double-blind, single-dose, two-treatment, two-period, two-sequence, crossover study was conducted in 48 healthy males. In each period, a single dose of LBEC0101 or Enbrel® was subcutaneously injected at 25 mg and serial blood samples for PK evaluation were collected up to 648 h post-dose. Serum etanercept concentrations and anti-drug antibodies (ADA) were measured using an enzyme-linked immunosorbent assay and an affinity capture elution assay. Log-transformed maximum concentration (C max) and area under the concentration-time curve (AUCinf) were compared. Tolerability was also evaluated. RESULTS: The serum concentration-time profiles were almost overlapped between LBEC0101 and Enbrel®. Geometric mean ratio (90% confidence intervals) for C max and AUCinf of LBEC0101 to Enbrel® were 1.02 (0.92-1.13) and 0.96 (0.87-1.05), respectively, which were within a conventional bioequivalence criteria of 0.80-1.25. ADA development was also comparable. Both drugs were well tolerated. CONCLUSIONS: LBEC0101 showed similar PK, immunogenicity, and tolerability profiles to Enbrel® after a single subcutaneous injection in healthy males. LBEC0101 can be further developed as a potential etanercept biosimilar (ClinicalTrial.gov identifier: NCT01725620).

The association between etanercept serum concentration and psoriasis severity is highly age-dependent.

The association between etanercept serum concentration and psoriasis disease severity is poorly investigated, and currently etanercept serum concentration monitoring that is aiming to optimize the psoriasis treatment lacks evidence. In this prospective study, we investigated the relation between etanercept exposure and disease severity via measuring etanercept concentrations at five consecutive time points in 56 psoriasis patients. Disease severity assessments included the Psoriasis Area and Severity Index (PASI), body surface area (BSA) and Physician Global Assessment (PGA), and etanercept and anti-etanercept antibody concentrations were determined every 3 months for a period of 1 year. The present study demonstrated that the association between etanercept concentration and psoriasis severity is age-dependent: when patients were stratified into three groups, patients in the youngest age group (-50 years) showed a lower PASI at a higher etanercept concentration (ß = -0.26), whereas patients in the oldest age group (+59 years) showed the opposite trend (ß =0.22). Similar age effects were observed in the relation of etanercept concentration with BSA (P=0.02) and PGA (P=0.02). The influence of age and length of time in therapy on the etanercept concentration-disease severity relation was unaffected by body mass index (BMI) or any other possible confounder. Incidence of anti-etanercept antibodies was low (2%). The age-dependent relation between etanercept serum concentrations is both unexpected and intriguing and needs further investigation.

An oral administration of a recombinant anti-TNF fusion protein is biologically active in the gut promoting regulatory T cells: Results of a phase I clinical trial using a novel oral anti-TNF alpha-based therapy.

BACKGROUND: An orally administered BY-2 plant cell-expressed recombinant anti-TNF fusion protein (PRX-106) consists of the soluble form of the human TNF receptor (TNFR) fused to the Fc component of a human IgG1 domain. Aim This study aim at determining the safety and the immune modulatory effect of an oral administration of PRX-106 in humans. METHODS: Three different doses (2, 8 or 16mg/day) of PRX-106 were orally administered for five consecutive days in 14 healthy volunteered participants. Subjects were followed for safety parameters and for an effect on T lymphocytes subsets and cytokine levels. RESULTS: An oral administration of PRX-106 was safe and well tolerated. The PK study showed that PRX106 is not absorbed. No effect on white blood cells and lymphocytes counts were noted. A dose dependent effect was noted on systemic lymphocytes. The oral administration of all three dosages was associated with an increase in CD4+CD25+ and CD8+CD25+ subset of suppressor lymphocytes. A marked increase in CD4+CD25+FoxP3 regulatory T cells was noted in the 8mg treated group. In addition, NKT regulatory cells, CD3+CD69+ and CD4+CD62 lymphocyte subsets increased with treatment. No changes in serum TNF alpha were observed. CONCLUSION: An oral administration of the non-absorbable recombinant anti-TNF fusion protein, PRX-106, is safe, not associated with immune suppression, while inducing a favorable anti-inflammatory immune modulation. The PRX-106 may provide a safe orally administered effective anti-TNF alpha-based immune therapy for inflammatory bowel diseases and non-alcoholic steatohepatitis, as well as other autoimmune, TNF-mediated diseases.

Impact of immunogenicity on response to anti-TNF therapy in moderate-to-severe plaque psoriasis: results of the PREDIR study.

PURPOSE: This study was conducted to examine the relationship between loss of clinical response to anti-tumor necrosis factor (TNF) therapy and the production of anti-drug antibodies (ADAs) and the potential effects of biologic immunogenicity. MATERIALS AND METHODS: This observational, non-interventional, cross-sectional study included patients with moderate-to-severe plaque psoriasis and secondary failure of adalimumab, etanercept and infliximab who were seen in the clinical practice setting. Clinical data and blood samples were collected after patient enrollment at the time that next doses of anti-TNF therapy were scheduled. ADA and serum drug concentrations were detected at a central reference laboratory using ELISA. RESULTS: Among 137 enrolled patients, ADA were identified in 31/65 (48%), 0/47 and 8/19 (42%) of patients treated with adalimumab, etanercept and infliximab, respectively. The presence of ADA was associated with a slightly worse clinical response in adalimumab-treated patients (Physician Global Assessment score: 3.7 vs. 3.2, ADA-positive vs. ADA-negative patients [p < .05]; correlation between serum ADA titer and body surface area: r = .292 [p = .019]). Concomitant DMARDs were not associated with anti-TNF immunogenicity in any treatment group. CONCLUSIONS: Additional evidence is needed from studies of anti-TNF therapy in psoriasis for clinicians to gain a better understanding of the impact of immunogenicity on clinical response.

Positive correlation between etanercept concentration and the decrease in Psoriasis Area and Severity Index scale value.

Background In the case of psoriatic patients, only a limited number of studies have related serum biological therapies and antidrug antibodies levels to clinical response. With respect to etanercept, the available evidence has not shown any relationship yet. Objective The aim of this study was to determine if there is any correlation among etanercept serum levels, the presence of anti-etanercept antibodies and clinical response to this treatment in psoriatic patients. Setting A 1500-bed hospital (A Coruña University Hospital Complex). Method A retrospective observational study in psoriatic patients treated with etanercept (50 mg once weekly) was carried out. Psoriasis Area and Severity Index scale and adverse reactions were recorded at the time of the extraction sample. The pharmacokinetic monitoring was evaluated at the previous time points by extracting peripheral blood samples before the dose administration. Etanercept and anti-etanercept antibodies concentrations were quantified by two sandwich-type ELISA immunoassays. The patients were classified into three groups (good, partial and nonresponders) in accordance with the treatment efficacy at the blood assessment moments. The Kruskall-Wallis test and Spearman correlation assay were used to assess the efficacy and incidence of adverse effects according to the etanercept concentration and anti-etanercept antibodies, considering p values of <0.05 as statistically significant. This statistical analysis was conducted using SPSS software (version19.0). Main outcome measures Etanercept and anti-etanercept antibodies trough serum levels and clinical response. Results 38 patients were included. 26 patients (68.4 %) were good, 5 (13.2 %) were partial and 7 (18.4 %) were non-responders. There was no significant difference with respect to etanercept levels: 2.7 µg/mL (range 0.7-5.6) versus 2.2 µg/mL (range 1.0-3.5) versus 1.73 µg/mL (range 0.1-2.3), respectively (p = 0.085). Nevertheless, a positive correlation between percentage decrease in the Psoriasis Area and Severity Index scale value with respect to the baseline value and etanercept concentration was found (p = 0.011). No anti-etanercept antibodies were detected; nor was there a significant difference in the incidence of adverse effects (p = 0.8523). Conclusions Our results showed a positive correlated between etanercept concentration and the percentage decrease in the Psoriasis Area and Severity Index scale value. The incidence of anti-etanercept antibodies in psoriatic patients was low.

Comparison of Three Assays to Quantify Infliximab, Adalimumab, and Etanercept Serum Concentrations.

BACKGROUND: To optimize treatment of inflammatory diseases, interest in the measurement of anti-tumor necrosis factor alpha (anti-TNFα) serum drug concentrations is increasing. Preferably, assays for the detection of these drugs should be compared using the same reference material. In this study, 2 commercially available enzyme-linked immunosorbent assays (ELISAs) and a commercially available bioassay for the determination of anti-TNFα drugs are compared. METHODS: Serum samples from infliximab-, adalimumab-, and etanercept-treated patients, control samples from ustekinumab-treated patients, and healthy donors were obtained. ELISAs manufactured by Sanquin and Theradiag and the iLite reporter gene-based bioassay from Biomonitor were compared. RESULTS: Sanquin, Theradiag, and iLite assays concordantly (100%) detected infliximab, adalimumab, and etanercept in the relevant patient groups. The Sanquin ELISAs specifically detected the anti-TNFα drug they were designed for, whereas the Theradiag and iLite showed cross-reactivity with other anti-TNFα drugs. Ustekinumab was not detected in any of the assays. Sanquin, Theradiag, and iLite exhibited linear quantitative correlation for all drug concentration assays. However, there were statistically significant quantitative differences in measured concentrations. CONCLUSIONS: All 3 commercially available assays seem suitable for therapeutic drug monitoring of anti-TNFα drugs, allowing sensitive and comparable detection of infliximab, adalimumab, and etanercept concentrations, however with differences in specificity and recovery.

Presence of antidrug antibodies correlates inversely with the plasma tumor necrosis factor (TNF)-α level and the efficacy of TNF-inhibitor therapy in psoriasis.

Antidrug antibodies have been shown to be associated with a loss of response during biologic therapy. Despite the potential association, there has been no report on the simultaneous monitoring of the following parameters in psoriasis: presence of neutralizing antibodies, plasma tumor necrosis factor (TNF)-α concentration, TNFi concentration and disease activity. Plasma concentrations of adalimumab, infliximab, etanercept and their respective antidrug antibodies, as well as plasma concentrations of TNF-α were measured in 77 psoriasis patients receiving biologic therapy, and the values were correlated with the clinical activity of the skin disease. Antidrug antibodies were identified in the plasma of 25% of infliximab-treated patients and 29.6% of adalimumab-treated patients, but not in the etanercept group. Clinical severity scores were significantly higher in the antibody-positive patients. In patients receiving infliximab or adalimumab therapy, the presence of antidrug antibodies was directly associated with reduced plasma TNF-inhibitor concentration and elevated plasma TNF-α level.