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Vol. 18. Issue 8.
Pages 475-479 (October 2022)
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Vol. 18. Issue 8.
Pages 475-479 (October 2022)
Brief Report
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Anti-TNFα drug levels in patients with rheumatoid arthritis and spondyloarthritis
Niveles de fármacos anti-TNFα en pacientes con artritis reumatoide y espondiloartritis
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Erardo Meriño-Ibarra
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eemerinnoi@salud.aragon.es

Corresponding author.
, Francisco Javier Manero Ruíz
Servicio de Reumatología, Hospital Universitario Miguel Servet, Zaragoza, Spain
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Abstract
Background and objectives

Knowledge of the levels of anti-TNFa drugs can modify treatment in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA).

Objectives

To compare the levels of anti-TNFa in patients with RA vs SpA, in different clinical situations.

Materials and methods

A retrospective, observational study was conducted. Levels of anti-TNFa and the presence of anti-drug antibodies were measured in consecutively selected patients, using the ELISA technique.

Results

Fifty-three, 73 and 78 patients treated with infliximab, adalimumab and etanercept were studied, respectively. The median drug levels in patients using standard doses were infliximab 2.2 µg/mL (1.4–5.2), adalimumab 4.9 µg/mL (0.8−8.9) and etanercept 3.1 µg/mL (2.3−4.4). There were no differences in drug levels according to disease activity but we found differences in etanercept and infliximab levels according to DMARD use.

Conclusions

Levels of anti-TNFa drugs will change with DMARD treatment.

Keywords:
Anti-TNFα levels
Rheumatoid arthritis
Spondyloarthritis
Resumen
Antecedentes y objetivos

El conocimiento de los niveles de fármacos anti-TNFα puede modificar el tratamiento en pacientes con artritis reumatoide (AR) y espondiloartritis (EspA).

Objetivos

Comparar los niveles de anti-TNFα en pacientes con AR vs EspA, en diferentes situaciones clínicas.

Materiales y métodos

Se realizó un estudio retrospectivo, observacional donde se midieron los niveles de anti-TNFα y la presencia de anticuerpos antifármacos en pacientes seleccionados consecutivamente, utilizando la técnica de ELISA.

Resultados

Se estudiaron 53, 73 y 78 pacientes en tratamiento con infliximab, adalimumab y etanercept, respectivamente. Los niveles medios de fármaco en pacientes con dosis estándar fueron: infliximab 2,2 μg/mL (1,4–5,2), adalimumab 4,9 μg/mL (0,8−8,9) y etanercept 3,1 μg/mL (2,3–4,4). No se encontraron diferencias en los niveles fármacos según la actividad de la enfermedad, sin embargo, hubo diferencias en los niveles de etanercept e infliximab según el uso de fármacos modificadores de la enfermedad sintéticos (FAMEsc).

Conclusiones

Los niveles de fármacos anti-TNFα se verán modificados por el tratamiento con FAMEsc.

Palabras clave:
Niveles de anti-TNFα
Artritis reumatoide
Espondiloartritis
Full Text
Introduction

In patients with rheumatoid arthritis (RA) treated with anti-TNF drugs (anti-TNF). A correlation has been found between drug levels and clinical response1. For example, in infliximab-treated patients, the presence of anti-drug antibodies (ADA) provoke loss of response, ifuional reactions and increased treatment withdrawal2. These data are not exclusive to RA and have also been described in spondyloarhritis (SpA), where anti-infliximab and anti-adalimumab antibodies are found in non-responders and in the case of infliximab, they are also related to infusional reactions, motivating a switch to another drug3.

Various drug level measurement techniques are available with different standardisation4, creating uncertainty as to the value of measuring drug levels. A consensus article has recently been published with the aim of reducing this uncertainty in the Spanish setting5.

The aims of this study were to compare anti-TNF levels in RA patients vs. SpA, in patients in remission/low disease activity (LDA) vs. non-remission/non-LDA according to rheumatic disease, and to determine the influence of the use of conventional synthetic disease-modifying drugs (DMARDs) on these levels.

Material and methods

A total of 474 patients were being treated with anti-TNF drugs at our centre, including 51 patients with infliximab, 198 patients with adlmumab, and 225 patients with etanercept. A retrospective, observational study was conducted to measure anti-TNF levels and the presence of ADA in a group of consecutively selected patients who attended consultations at the rheumatology department of the Miguel Servet University Hospital.

Inclusion criteria

  • Adult patients on anti-TNF treatment.

Exclusion criteria

  • Patients who declined to participate in the study

  • Patients under follow-up in other hospitals

  • Diagnoses other than RA or SpA

The most commonly used methods for measuring levels are the sandwich ELISA and the indirect ELISA4. In our study, the sample was obtained on the day the drug was due to be administered (trough level), using the Promonitor® test from Laboratorios Grifols (sandwich ELISA), and according to the methodology described by Chen DY et al.1. In cases with undetectable anti-TNF levels, Acaf was measured using the Promonitor® test from Laboratorios Grifols (bridge-type ELISA).

The following data were collected from the patients’ clinical history:

  • Time of evolution of the disease

  • Type and schedule of biologic treatment and DMARDs

  • Adherence: percentage of the prescribed dosage of the drug that the patient withdraws from the hospital pharmacy.

  • Disease activity: considering remission/low activity in patients with RA when they had a DAS28 (CRP) ≤ 3.2 and in patients with SpA a BASDAI ≤ 4 and ASDAS (CRP) ≤ 2.1. The activity indices were obtained from the consultation prior to the measurement of the levels.

With these data, a group of patients with RA and SpA was obtained and in each, subgroups with drug dosages according to the technical data sheet (standard dose) and others with dosages lower than those recommended (suboptimal dose), as well as patients with/without treatment with DMARDs.

Ethical aspects

All patients signed an informed consent form for this study and for the use of biological samples for biomedical research. This study was approved by the Research Ethics Committee of the Autonomous Community of Aragon.

Statistical method

Quantitative variables: distribution was determined with the Kolmogorov-Smirnov statistic (Lilliefors correction); in variables with N < 50, the Shapiro–Wilk statistic was applied; if the distribution was normal, the mean and standard deviation (SD) were determined; in variables with non-parametric distribution, the median and interquartile range (IQR) were determined. For differences between means and between medians: Student’s t test and Mann–Whitney U test were used, respectively. For qualitative variables: 2 × 2 contingency tables with Pearson’s Chi-square test. Statistical procedures were performed with the R statistical programme and calculated with a 95% confidence interval.

Results

A total of 53, 73, and 78 patients on treatment with infliximab, adalimumab, and etanercept, respectively, were studied. In all cases, a single sample extraction was performed. Eleven patients were excluded due to AFA and absence of drug levels: 3 (5.6%) treated with infliximab, all with SpA, none treated with DMARDs; 8 (11%) treated with adalimumab, 2 with RA on leflunomide, 6 patients with SpA, one treated with leflunomide, the remaining 5 without DMARDs. No anti-etanercept antibodies were detected.

No differences were found in drug levels according to disease type and disease activity. Patients with RA had a median DAS28: 2.79 (RI: 2.27−3.62) and those with SpA had a BASDAI of 3.47 (SD: 2.2) and an ASDAS of 1.70 (1.40−2.27). The variables studied are displayed in Table 1.

Table 1.

Summary of variables assessed, by rheumatic disease.

Variable  Rheumatoid arthritis  Spondyloarthritis  Total  P value 
  N = 74  N = 119  N = 193   
Age (years)a  59.8 (12.6)  54.7 (14.0)  56.7 (13.7)  .011 
Women, N (%)  57 (77)  44 (36.9)  101 (52.3)  .000 
Infliximab (g/mL)  2.10 (1.70−3.50)  2.9 (0.85−6.50)  2.3 (1.0−5.80)  .546 
Adalimumab (g/mL)  2.80 (1.80−6.10)  5.40 (1.50−8.95)  3.80 (1.80−8.60)  .272 
Etanercept (g/mL)  2.60 (1.20−4.00)  2.0 (.83−3.20)  2.40 (1.0−3.45)  .200 
Biological therapy, N  74  119  193  .022 
Infliximab, N (%)  16 (21.6)  34 (28.6)  50 (25.9)   
Adalimumab, N (%)  19 (25.7)  46 (38.6)  65 (33.7)   
Etanercept, N (%)  39 (52.7)  39 (32.8)  78 (40.4)   
Time to disease progression, (years)  12.6 (8.20−21.4)  13.1 (6.64−22.9)  12.9 (7.49−22.5)  .877 
Time on biologic therapy, (years)  5.87 (2.05−9.53)  4.20 (1.80−9.14)  4.85 (1.82−9.26)  .386 
BMI, (kg/m2)  26.2 (22.6−29.1)  25.8 (23.3−29.8)  26.1 (23.1−29.6)  .325 
CRP, (mg/dl)  .27 (.13−.70)  .24 (.11−.58)  .26 (.13−.61)  .555 
DAS28, (CRP)  2.79 (2.27−3.62)  —  2,79 (2,27−3,62)   
BASDAIa  —  3.47 (2.2)  3.47 (2.2)   
ASDAS, (CRP)  —  1.70 (1.40−2.27)  1.70 (1.40−2.27)   
DMARDs, N (%)  50 (67.5)  27 (22.6)  77 (39.8)  .000 
Methotrexate, N (%)  33 (44.5)  19 (15.9)  52 (26.9)   
Leflunomide, N (%)  16 (21.6)  5 (4.2)  21 (10.8)   
Sulphasalazine, N (%)  1 (1.63)  3 (2.53)  4 (2.1)   
Cases with suboptimal dose of anti-TNF, N (%)  26 (35.1)  39 (32.7)  65 (33.6)  .735 
Infliximab, N (%)  5 (6.7)  9 (7.56)  14 (7.25)   
Adalimumab, N (%)  5 (6.7)  14 (11.7)  19 (9.84)   
Etanercept, N (%)  16 (21.6)  16 (13.4)  32 (16.5)   
Remission/low activity, N (%)  55 (74.3)  88 (77.8)  143 (76.5)  .575 

ASDAS: Ankylosing Spondylitis Disease Activity Score; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BMI: Body Mass Index; CRP: C-reactive protein; DAS28: Disease Activity Score 28-joint counts; DMARDs: synthetic disease-modifying drugs.

a

Data expressed as mean (standard deviation), other continuous quantitative variables expressed as median (interquartile range).

The percentage of remission/LDA in cases with RA and SpA was 74.3% and 77.8%, respectively. The time of disease progression was 12.9 years (RI: 7.49−22.5), with no differences between diseases (Table 1); adherence was ≥80% in 88.6% of cases.

Drug levels in patients on standard-dose anti-TNF were 2.2 g/mL (1.4–5.2), 4.9 g/mL (0.8−8.9), and 3.1 g/mL (2.3−4.4) for infliximab, adalimumab and etanercept, respectively (Table 2A), with no differences according to rheumatic disease (data not shown). We also found no differences in the group of cases with standard drug dosages, segmented by disease type and activity (Table 2B). When dividing patients with standard drug dosages according to treatment with/without DMARDs, we obtained significant differences in serum levels of infliximab and etanercept; adalimumab levels were similar in both groups (Table 2C), and subdividing these cases according to rheumatic disease, only etanercept levels exhibited differences in patients with SpA (Table 2C1).

Table 2.

Anti-TNF drug levels in standard-dose patients. A: Overall results. B: Anti-TNF drug levels according to rheumatic disease and according to remission/low disease activity vs. no remission/no low disease activity. C: Drug levels according to treatment with DMARDs and C1 according to rheumatic disease.

A  anti-TNFα levels (μg/mL), N = 128 
Infliximab  2.2 (1.4−5.25) 
Adalimumab  4.9 (.8−8.9) 
Etanercept  3.1 (2.3−4.4) 
B  Remission/LDA vs. no remission/no LDA 
  Rheumatoid arthritis N = 48 
  Remission/LDA N = 33  No remission/no LDA N = 15  P value 
Infliximab  2.0 (1.5−2.8)  3.4 (3.4−3.4)  .427 
Adalimumab  6.4 (2.8−8.0)  2.0 (0.23−3.4)  .128 
Etanercept  2.7 (2.3−4.2)  4.0 (3.1−4.3)  .366 
  Spondyloarthritis N = 80 
  Remission/LDA N = 55  No remission/no LDA N = 25  P value 
Infliximab  4.4 (1.4−7.55)  2.4(1.0−6.2)  .563 
Adalimumab  6.6 (0.45−9.95)  7.2 (1.85−8.9)  .999 
Etanercept  2.8 (2.4−3.4)  4.2 (2.35−6.65)  .219 
C  DMARDs N = 52  No DMARDs N = 76  P value 
Infliximab  4.0 (2.2−6.0)  1.8 (1.0−2.4)  .035 
Adalimumab  4.2 (.7−8.8)  4.9 (1.2−9.1)  .607 
Etanercept  3.4 (2.6−4.7)  2.5 (1.8−3.7)  .039 
C1  Rheumatoid arthritis N = 48 
  DMARDs N = 32  No DMARDs N = 16  P value 
Infliximab  2.2 (1.8−5.2)  2.0 (1.55−2.75)  .520 
Adalimumab  1.9 (0.7−7.45)  3.9 (3.55−4.8)  .539 
Etanercept  3.2 (2.6−4.2)  3.2 (1.95−4.9)  .833 
  Spondyloarthritis N = 80 
  DMARDs N = 20  No DMARDs N = 60  P value 
Infliximab  5.4 (3.4−7.4)  2.1 (0.95−6.65)  .223 
Adalimumab  9.3 (6.6−10.2)  6.3 (0.55−9.7)  .607 
Etanercept  4.4 (3.3−6.1)  2.5 (1.95−3.25)  .008 

LDA: low disease activity; DMARDs: synthetic disease-modifying drugs.

Results expressed as median (interquartile range).

Discussion

The drug level achieved after the standard treatment regimen may differ from one patient to another; however, the drug level required to achieve remission may not differ, hence the importance of evidence to support monitoring of anti-TNF6 levels.

The patients studied were fairly homogeneous, even between those in remission and non-remission; for instance, RA patients had generally low activity indices, which may have contributed to differences in drug levels not being conspicuous when comparing patient subgroups.

With respect to infliximab, the study by Jurado T et al. found that most RA patients in remission at week 54 after perfusion displayed levels of 4.4 g/mL at week6,7 whereas in our study at week 12, we logically found lower levels of infliximab, with no differences in the remission/LDA vs. non-remission/non-LDA groups. Our results show no difference between infliximab levels between RA and SpA; nevertheless, Padilla-Martínez EM et al. detected different infliximab trough levels between the 2 diseases8, but did not exclude cases with ADA from the analysis; similarly, they had a smaller sample size.

Sanmarti R et al. found adalimumab levels of 6.9 g/mL in patients with RA in remission9. Pouw MF et al. suggest that they should have levels of between 5−8 g/mL10, similar to what was found in our study in patients in remission. Finally, Kneepkens EL et al. obtained an etanercept level of 3.8 g/mL (2.5–5.2) in SpA patients with ASDAS < 2.111 and Sanmarti R et al. obtained etanercept levels of 2.3 g/mL in RA patients in remission9. Our results were similar in both diseases excluding patients with suboptimal doses.

Anti-TNF levels can be affected by different factors such as comorbidity, route of drug administration, ADA formation, or the use of cSFs12. In our study, we detected differences in drug levels between patients with/without cAMP for infliximab and etanercept; nonetheless, we found no differences for adalimumab levels. However, Vogelzang EH et al. found higher levels of adalimumab in patients with RA or psoriatic arthritis treated with methotrexate13.

In general, we did not find differences in drug levels according to disease activity, perhaps because of the homogeneity of the sample in this aspect, but if we add a cSF-MEF, then differences do emerge, mainly in SpA. Does this suggest the need to always use cSF-MEFs in association with anti-TNFs? Probably not routinely, albeit this opinion might be different if we assessed other biomarkers, such as the CXCL12 genotype or HLA-DQA1*0514,15.

One of the limitations of our study is that as it is observational, retrospective, and conducted in clinical practice. As such, we do not aways have the results for all the variables studied. In addition, when the sample was subdivided, it was reduced, in some cases losing representativeness of the population under study.

In summary, we purport that anti-TNF drug levels will be modified by treatment with cAMP.

Funding

This research has not received any specific public or private funding.

Conflict of interest

None.

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Please cite this article as: Meriño-Ibarra E, Manero Ruíz FJ. Niveles de fármacos anti-TNFα en pacientes con artritis reumatoide y espondiloartritis. Reumatol Clín. 2022;18:475–479.

Copyright © 2021. Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología
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