Obesity decreases clinical efficacy and levels of adalimumab in patients with ankylosing spondylitis.

OBJECTIVES: Obesity can be a factor that affects response to anti-TNF drugs. However, studies on patients with ankylosing spondylitis (AS) are rare. We aimed to determine whether obesity affects serum levels of adalimumab (ADL), and immunogenicity and clinical efficacy of the drug in patients with AS. METHODS: A cross-sectional study on 57 patients with axial AS receiving ADL was conducted. They received DMARD per standard of care at their rheumatologist's discretion. Patients' body mass index (BMI) was obtained when ADL treatment began. Clinical response was evaluated using the Spanish versions of the BASDAI index and the ASDAS ESR index. Serum concentrations of free ADL (trough level) and anti-ADL antibodies were measured using Promonitor-ADL and Promonitor Anti-ADL ELISA kits (Progenika Grifols SA, Spain), just prior to the next subcutaneous injection of ADL. RESULTS: Patients with BMI >30 kg/ m2 (obese) as opposed to BMI <25 kg/ m2 (normal), presented lower blood ADL levels [5.0 (5.52) vs. 9.14 (4.3), p=0.032], increased ASDAS scores (2.58 [0.79] vs. 1.9 [0.83], p=0.03), and shorter ADL treatment time: 1.01 [0.84] vs. (1.85 [1.65]; p=0.08]), and increased BASDAI results (5.04 [2.5] vs. 3.5 [1.88]; p=0.06). Obese patients showed a lower probability of clinical response to ADL versus non-obese patients with regard to achieving BASDAI ≤4 (OR: 3.5, 95%CI: 0.84-17.19; p=0.05) or ASDAS ≤2.1 (OR: 4.64, 95%CI: 1.02-24.13; p=0.02). CONCLUSIONS: Of the AS patients receiving treatment with ADL, those that are obese had significantly lower serum ADL levels and decreased clinical response without an increase in immunogenicity.

Antibodies to infliximab in Remicade-treated rheumatic patients show identical reactivity towards biosimilars.

OBJECTIVES: The aim of this study was to determine whether antibodies to infliximab (IFX) in Remicade-treated patients cross-react with the biosimilar CT-P13. METHODS: 250 consecutive patients with rheumatic diseases under Remicade and 77 controls were retrospectively selected for the study. Anti-IFX antibodies at drug through levels were measured in parallel with three different bridging ELISA assays: Promonitor-ANTI-IFX kit, which uses Remicade to detect antibodies, and two more assays that use either Inflectra or Remsima with the same format. Correlation and association between each assay was studied. RESULTS: 50.4% of patients were tested positive with Promonitor-ANTI-IFX. All were antibodies to IFX (ATI)-positive when either Inflectra or Remsima assays were used. In all comparisons positive and negative percentage agreements were 100%, and correlation coefficients were ≥0.995. No differences between rheumatoid arthritis and spondyloarthritis, or between concomitant immunosuppressives, were observed. CONCLUSIONS: Anti-IFX antibodies of Remicade-treated patients cross-react with either Inflectra or Remsima. Although additional epitopes may be present in the biosimilar, results suggest that epitopes influencing the immune response to IFX are also present in the biosimilar. Antibody-positive patients treated with Remicade should not be switched to the biosimilar, since antibodies will interact with the new drug and potentially lead to loss of response. This finding supports the utility for therapeutic drug monitoring before a switching strategy is considered.

Clinical relevance of monitoring serum levels of adalimumab in patients with rheumatoid arthritis in daily practice.

OBJECTIVES: The aim of this paper is to assess the usefulness of measuring serum levels of adalimumab (ADL) and anti-ADL antibodies in 57 patients with rheumatoid arthritis (RA) treated with ADL for at least 3 months in daily practice. METHODS: All patients received concomitant disease-modifying anti-rheumatic drug (DMARD). Receiver-operator characteristics (ROC) analysis was used to obtain the cut-off value of ADL for low disease activity (DAS28-ESR ≤3.2). RESULTS: Anti-ADL antibodies were detected in 4 (7%) patients with a mean (SD) DAS28 score of 4.6 (0.9). Patients with positive anti-ADL antibodies had significantly lower levels of ADL and higher DAS28 scores than those with negative antibodies. Patients with DAS28 ≤3.2 as compared with patients with DAS28 >3.2 showed significantly better SDAI score, higher serum concentrations of ADL and none of them showed anti-ADL antibodies. The cut-off of serum level of ADL for DAS28 <3.2 was 4.3 mg/L. According to serum levels of ADL, patients were grouped into group 1 (low level) <5.5 mg/L, group 2 (medium level) 5.5-11.3 mg/L and group 3 (high level) >11.3 mg/L. Patients in the medium group were closed to clinical remission (median DAS28 2.7) and patients in the high group were on clinical remission (DAS28 2.1). CONCLUSIONS: Serum levels of ADL should be maintained >4.3 mg/L. In patients with ADL levels >11.3 mg/L, a decrease of the dose of ADL or an increase in the interval between doses may be planned. The presence of anti-ADL antibodies was associated with a loss of clinical efficacy of ADL.

Practical application of acid dissociation in monitoring patients treated with adalimumab.

Patients treated with adalimumab (ADL) can induce anti-ADL antibodies (AAA) formation that is associated with low drug levels and clinical non-response. But, in the majority of the assays, the measurement of AAA is hampered by the presence of the drug itself. In support of immunogenicity assessment in clinical samples with subtherapeutic ADL levels, we proved acid pre-treatment for AAA detection with the Promonitor-enzyme-linked immunosorbent assay (ELISA). Were measured AAA after acidification in 32 serum samples with a subtherapeutic ADL trough level. ADL and AAA concentrations were measured by ELISA (Promonitor). The impact of drug concentration on AAA recovery (with or without acidification) was also evaluated by mixing known amounts of ADL (0.25, 0.5 and 1 mg/L) and AAA (100, 200, 300 and 400 AU/mL) from clinical samples in pooled serum. The drug significantly inhibited the detection of AAA in untreated samples. And progressively higher levels of ADL cause increasing inhibition of signal. Acid pre-treatment carried a significant increase in assay response, particularly at lower free ADL concentrations. AAA were detected in the 53 % of the samples after acid dissociation. In seven patients, the positive AAA after dissociation was detected in the first monitoring of ADL and five patients were positive 3 months later for AAA with the standard assay. Monitoring AAA using acid dissociation in patients with subtherapeutic circulating level of ADL could detect precocious problems of bioavailability, assess the immunogenicity of ADL and may be used to optimise dose regimens, thereby preventing prolonged use of inadequate therapy and guide change of treatment.

Comparative study of both versions of an immunoassay commercialized for therapeutic drug monitoring of adalimumab in rheumatoid arthritis.

OBJECTIVE: To describe the results of the comparative study between both versions of an immunoassay commercialized for therapeutic drug monitoring of adalimumab (ADA) in rheumatoid arthritis (AR). MATERIAL AND METHODS: 140 samples of patients with RA treated with ADA 40mg every 14 days were analyzed by both versions of the test (V1 or previous and V2 or updated). RESULTS: A good correlation was obtained by both versions. In general V2 provides higher results of ADA's concentration than V1 and presents greater precision in the range of concentrations for clinical decisions, adjusting for the real concentration of the drug in blood. In addition, V2 allows for complete automation, which simplifies the analysis and reduces significantly the variability. CONCLUSION: ADA's monitoring with the updated version demonstrated to have technical significant advantages, constituting a more practical tool for therapeutic decisions in patients with RA.

Estudio comparativo de las 2 versiones de un inmunoanálisis comercializado para la monitorización terapéutica de adalimumab en artritis reumatoide / Comparative study of both versions of an immunoassay commercialized for therapeutic drug monitoring of adalimumab in rheumatoid arthritis

Objetivo: Describir los resultados del estudio comparativo entre las 2 versiones de un inmunoanálisis comercializado para la monitorización terapéutica de adalimumab (ADA) en artritis reumatoide (AR). Material y métodos: Se han analizado 140 muestras de suero de pacientes con AR tratados con ADA 40 mg cada 14 días con las 2 versiones del ensayo (V1 o anterior y V2 o actualizada). Resultados: Se obtuvo una buena correlación con las dos versiones. En general, V2 proporciona resultados más altos de concentración de ADA que V1 y presenta una mayor precisión en el rango de concentraciones próximas al nivel de decisión clínica, ajustándose más a la concentración real del fármaco en sangre. Además, permite la automatización completa, lo cual simplifica mucho el análisis, y reduce significativamente la variabilidad. Conclusión: La monitorización de ADA con la versión actualizada demostró tener ventajas técnicas significativas, pudiendo ser una herramienta más práctica para la toma de decisiones terapéuticas en pacientes con AR (AU)

Objective: To describe the results of the comparative study between both versions of an immunoassay commercialized for therapeutic drug monitoring of adalimumab (ADA) in rheumatoid arthritis (AR). Material and methods: 140 samples of patients with RA treated with ADA 40 mg every 14 days were analyzed by both versions of the test (V1 or previous and V2 or updated). Results: A good correlation was obtained by both versions. In general V2 provides higher results of ADA’s concentration than V1 and presents greater precision in the range of concentrations for clinical decisions, adjusting for the real concentration of the drug in blood. In addition, V2 allows for complete automation, which simplifies the analysis and reduces significantly the variability. Conclusion: ADA’s monitoring with the updated version demonstrated to have technical significant advantages, constituting a more practical tool for therapeutic decisions in patients with RA (AU)

Tratamiento con fármacos anti-TNF: utilidad de la monitorización de niveles de fármaco y anticuerpos antifármaco en la práctica clínica / Anti-tumor necrosis factor drug therapy: The usefulness of monitoring drug levels and anti-drug antibodies in clinical practice

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Acute cholestatic hepatitis probably associated with risperidone.

OBJECTIVE: Risperidone is an atypical neuroleptic drug widely used due to the lower incidence and severity of hepatic adverse effects in comparison to phenothiazines. Although idiosyncratic reversible hepatotoxicity may occur in association with risperidone, the interaction with fluoxetine might increase the risk of toxic liver injury in a vulnerable patient. METHODS AND RESULTS: We present a case of acute cholestatic hepatitis probably associated with the use of risperidone after only a few days of therapy in a patient also treated with fluoxetine. The patient, a 64-year-old male, developed a rapid increase in liver enzymes after starting treatment with only four doses of risperidone 2 mg/day. CONCLUSIONS: We recommend obtaining baseline liver function tests before starting risperidone and regular monitoring to screen patients for liver damage during therapy whenever a patient is also receiving fluoxetine.