Abstract
Scand J Rheumatol 2018;47:345–350 345 Concentrations of infliximab and anti-drug antibodies in relation to clinical response in patients with rheumatoid arthritis 1 1 2 1 F Siljehult , L Ärlestig , C Eriksson , S Rantapää-Dahlqvist Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden Department of Clinical Immunology/Clinical Microbiology, Umeå University, Umeå, Sweden Objective: The efficacy of anti-tumour necrosis factor-α (anti-TNF-α) treatment with infliximab (IFX) may be reduced by the development of anti-drug antibodies (ADAs). This study evaluated drug concentration and the presence of ADAs, relative to response, in rheumatoid arthritis (RA) patients treated with IFX. Method: Ninety-four RA patients were consecutively included and assessed for disease activity at baseline, and after 14, and 30 or 52 weeks. Serum IFX concentration and ADAs were analysed using in-house enzyme-linked immunosorbent assays. ADA analysis was based on binding to TNF-α-coated plates, with the lower detection limit set at mean + 2 sd of controls. Results: At 14 and 52 weeks, 74.5% of the patients had moderate to good response. Good responders had significantly higher IFX concentrations than moderate and poor responders at 52 weeks (6.6 ± 1.4 µg/mL vs 3.6 ± 1.3 µg/mL and 2.6 ± 1.6 µg/mL, respectively). An IFX concentration ≥4.66 µg/mL at 14 weeks yielded a moderate to good response at 30/52 weeks, with 91.3% specificity and 39.3% sensitivity. Eleven patients dropped out owing to lack of efficacy and eight owing to side effects; three with IFX concentration ≤ 0.5 µg/mL were ADA positive. At an IFX concentration ≤ 0.5 µg/mL, 43.8% and 30.1% at 14 and 52 weeks, respectively, were ADA positive. None of the good responders had ADAs. Conclusion: One-quarter of patients had an IFX concentration ≤ 0.5 µg/mL but only 11.7% had ADAs. High IFX concentration was related to a good response, suggesting that the lack of response could be due to a lack of IFX, rather than to the presence of ADAs. Rheumatoid arthritis (RA) is a chronic autoimmune Method inflammatory disease characterized by joint inflamma- Ninety-four (78 female and 16 male) patients fulfilling the tion, with a prevalence of 0.5–1% (1, 2). Tumour necro- 1987 American Rheumatism Association criteria for RA sis factor-α (TNF-α) has been identified as having a key (10) were consecutively included in the study between role in the inflammatory process and, consequently, the 1999 and 2006. The patients were treated with IFX at introduction of TNF-α blockade by drugs such as inflixi- baseline, at 2 and 6 weeks, and thereafter every 8 weeks. mab (IFX) has led to successful treatment of the disease The patients were followed for 52 weeks, although in 19 (3). However, sometimes IFX fails to produce a satisfac- patients the IFX treatment was terminated before the fol- tory clinical response in patients with RA, and this is low-up reached 52 weeks owing to side effects (n = 8) or frequently reported as being due to the generation of lack of efficacy (n = 11). anti-drug antibodies (ADAs) or to other side effects (4, Patients were assessed before the infusion at baseline, and 5). Previous studies have shown that up to 44% of after14and 52 weeks, fornumberofswollen and tender patients treated with IFX develop ADAs (4, 6–8). Too joints, erythrocyte sedimentation rate (ESR; mm/h), patients’ low a treatment dosage in relation to disease activity or global assessment, Disease Activity Score based on 28-joint an increased metabolism of IFX could also affect the count (DAS28), and response to treatment (11, 12). C-reac- response to the drug (9). tive protein (CRP; mg/mL) was measured. Data on treatment In this study, we evaluated the response to IFX treatment with disease-modifying anti-rheumatic drugs (DMARDs: in relation to the concentration of IFX and the presence of methotrexate, sulfasalazine, leflunomide, azathioprine, and ADAs during treatment in consecutively included patients cyclosporine), and with oral glucocorticoids (prednisolone- with RA in clinical practice. equivalent dosage < 10 mg/day) were also registered. All data were collected into the Swedish National Quality Reg- ister, a register for patients treated with biologics. Supple- Solbritt Rantapää-Dahlqvist, Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, SE-90185 Umeå, Sweden. mentary data were also retrieved from the patients’ medical E-mail: [email protected] records. Data on the patients are presented in Table 1. Accepted 23 January 2018 Plasma was sampled before every infusion, at baseline, and © 2018 The Author(s). Published by lnforma UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/ licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. DOI: https://doi.org/10.1080/03009742.2018.1433232 www.scandjrheumatol.dk 346 F Siljehult et al Table 1. Patient characteristics at baseline. ADAs was set at the mean value + 2 sd of the percentage of inhibition of binding by the plasma from healthy indivi- Characteristics (n = 94) Value duals. We tested 39 healthy individuals and the mean value + 2 sd resulted in a cut-off value of 28.88% of inhibition, Age at disease onset (years), mean ± sd 41.6 ± 11.8 Disease duration (years), mean ± sd 14.3 ± 10.7 which is in agreement with the original presentations for Females, n (%) 78 (83) the method (9, 13). BMI (kg/m ), mean ± sd 24.9 ± 4.5 Dose IFX (mg/kg), mean ± sd 3.3 ± 0.6 RF positive*, n (%) 89 (95) Anti-CCP antibody positive†, n (%) 84 (88) Statistical analysis ANA positive‡, n (%) 22 (23.7) Non-parametric tests were used for comparative analyses DAS28, mean ± sd 5.6 ± 1.3 Swollen joint count, median (IQR) 8 (4–13) between continuous data. The Mann–Whitney U-test Tender joint count, median (IQR) 9 (4–13) was used to analyse two groups, the Kruskal–Wallis ESR (mm/h), mean ± sd 38.6 ± 23.5 test for more than two groups, and Friedman’s test for CRP (mg/L), mean ± sd 32.3 ± 28.9 related samples. Univariate analyses of variance were DMARDs, n (%) 90 (95.7) used to investigate the relative strengths of the relation- MTX, n (%) 72 (76.6) Glucocorticoids, n (%) 45 (47.9) ships between the variables and outcome. The receiver operating characteristics curve was used to determine the *Rheumatoid factor (RF) was measured using an in-house optimal value of IFX for moderate to good response at Waaler–Rose haemagglutination protocol. 52 weeks. All statistical analyses were performed using †Cyclic citrullinated peptide (CCP) was assessed according to the manufacturer’s protocol (anti-CCP2 test; Euro Diagnostica, SPSS 21.0 software (IBM Corp., Armonk, NY, USA). Malmö, Sweden). ‡Antinuclear antibodies (ANA) were analysed using indirect immunofluorescence on HEp2-glass slides (Immunoconcept, Results Sacramento, CA, USA). BMI, body mass index; DAS28, Disease Activity Score based on 28- IFX levels and clinical response joint count; IQR, interquartile range; ESR, erythrocyte sedimenta- tion rate, CRP, C-reactive protein; DMARDs, disease-modifying This study included 94 patients with RA, 72 of whom anti-rheumatic drugs (methotrexate, sulfasalazine, leflunomide, were followed and sampled for 52 weeks and another azathioprine, and cyclosporine); MTX, methotrexate. five for 30 weeks, while 17 patients were, in addition to baseline measures, sampled only at 14 weeks. After 14 weeks, 70 of 94 patients (74.5%) had moderate to at 14, and 30 or 52 weeks, and stored at −80°C until good response (as defined by European League Against analysed. Three patients were lost from sampling at Rheumatism criteria), with similar results at week 52, 52 weeks. when 54 of 72 patients (75.0%) had a moderate to good The initial treatment dose of IFX was 3.3 ± 0.1 mg/kg response (Figure 1). (mean ± sem). If no satisfactory response was achieved, Good responders had significantly higher concentra- the dose was increased, in eight patients between weeks tions of IFX, e.g. at 52 weeks good responders had an 6 and 14, and in 13 patients before their last infusion. IFX concentration of 6.6 ± 1.4 µg/mL, compared with Furthermore, the treatment intervals between infusions 3.6 ± 1.3 µg/mL in patients with a moderate response and were decreased for 19 patients between 6 and 14 weeks 2.6 ± 1.6 µg/mL in those with a poor response (p < 0.001) and for 31 patients before 30/52 weeks. The adjustments (Figure 2). An IFX concentration ≥ 4.66 µg/mL at 14 weeks to achieve low or no disease activity were decided by the patient’s treating physician. Therapeutic response All patients gave their informed consent to participate and 100% the regional ethics committee approved the study. 90% 80% 70% Analyses of levels of IFX and ADAs 60% 50% The levels of IFX and ADAs were analysed for all samples on one occasion after 52 weeks using in-house enzyme- 40% linked immunosorbent assays (ELISAs), as previously 30% developed and described by Marits et al (9). The method 20% for analysing IFX concentration using TNF-α-coated plates 10% was performed as previously described (9, 13, 14). ADAs 0% 14w 52w were analysed when the trough concentration of IFX was no moderate good response ≤ 0.5 µg/mL before the next infusion. The ELISA for the ADA analysis was based on inhibition of binding of IFX to Figure 1. Frequencies of therapeutic response at 14 and 52 weeks after treatment with infliximab. the ELISA plates coated with TNF-α. The cut-off level for www.scandjrheumatol.dk Infliximab and antidrug antibodies in RA 347 25 dose of IFX was increased significantly during the ns p < 0.001 treatment period, from 3.3 ± 0.1 mg/kg at baseline to 3.4 ± 0.1 mg/kg at 14 weeks and 3.6 ± 0.1 mg/kg at 52 weeks, and was unrelated to the therapeutic response and presence of ADAs (Friedman p < 0.001). There was no correlation between the dose in mg/kg and the measured concentration of 5 IFX at either 14 or 52 weeks. Twelve of the 16 patients with an IFX concentration ≤ 0.5 µg/mL were analysed on one later occasion (30 or 52 weeks), with 10 exhibiting an IFX concentration ≤ 0.5 µg/mL, and -5 seven of the 12 patients (58%) were ADA positive. In No Moderate Good No Moderate Good response most of these cases (11/12), the dose of IFX given 14 weeks 52 weeks was constant, but in one patient who was positive for ADAsafter 14 weeksthe dose wasincreased from Figure 2. Infliximab concentrations (IFX conc) at 14 and 52 weeks, 180 mg to 300 mg; the ADA positivity was lost respectively, stratified by response to treatment. ns, not significant. despite a low IFX concentration (≤ 0.5 µg/mL) being detected. predicted a moderate to good response at 52 weeks, with a specificity of 91.3% and a sensitivity of 39.3% (area under the curve 0.689). Patients with a good response at 14 weeks Clinical response and ADAs and an IFX concentration > 0.5 µg/mL were still good to moderate responders after 52 weeks (16/18; 88.9%), Non-responding patients after 52 weeks were significantly while those with an IFX concentration ≤ 0.5 µg/mL more often ADA positive (23.8% vs moderate to good did not improve their response from week 14 to week responders 7.3%, p = 0.046). None of the patients who 52, despite the dose of IFX being increased from were good responders at 14 or at 52 weeks or in remission (mean ± sd) 220.6 ± 49.1 mg to 235.7 ± 49.7 mg (26.4%; DAS28 < 2.6) was ADA positive. Seven patients (p = 0.066) or 3.24 ± 0.62 mg/kg to 3.54 ± 0.77 mg/kg, out of 16 (44%) with low IFX concentration at week 14 respectively (Figure 3). were ADA positive; this represents 7.4% of all patients who The concentration of IFX was inversely correlated started with IFX therapy. At 30 weeks, in two of the five with DAS28, and with levels of ESR and CRP at patients who terminated early, the infusions were ADA 14 weeks (p < 0.01, p < 0.05, and p < 0.001, respec- positive, and at 52 weeks six other patients (10.4%) with tively) and 52 weeks (p < 0.001 for all three ana- an IFX concentration of ≤ 0.5 µg/mL were ADA positive. In lyses). At week 14, 16 of 94 patients (17%) had an total, 11 (11.7%) of the patients were ADA positive at 14 or IFX concentration ≤ 0.5 µg/mL in the analysed sam- 52 weeks and four patients were positive on both occasions. ples. After 30 or 52 weeks, 26 of 77 patients (33.8%) These individuals were significantly more often non-respon- had an IFX concentration ≤ 0.5 µg/mL. The treatment ders (56.0% vs those with higher concentrations 12.0%, chi- square 17.14, p < 0.001). 60% ADA-positive patients had significantly higher DAS28 scores at both 14 and 52 weeks and signifi- 50% cantly higher CRP levels at 52 weeks. The presence of ADAs was unrelated to positivity for antibodies [anti- citrullinated protein antibody (ACPA), rheumatoid fac- 40% tor (RF), antinuclear antibodies (ANAs), or double- stranded DNA antibodies], age, gender, body mass 30% index (BMI), or smoking. The treatment dose of IFX, in total or per kilogram, did not affect the pre- 20% sence of ADAs. Treatment with DMARDs (in 95% and 97% of cases at 14 and 52 weeks, respectively) 10% and/or prednisolone (in 35% and 46% at 14 and 52 weeks, respectively) did not affect the presence of 0% ≤0.5 >0.5 ≤0.5 >0.5 ADAs. In 72%and 77%of patients at14and 14w 52w 52w 14w 52 weeks, respectively, the treatment was methotrex- ate (mean dose 11.3 ± 4.7 mg/week). The correspond- No Moderate Good ing figures for corticosteroid treatment were 14.3% in Figure 3. Response to treatment stratified by infliximab concentration ADA-positive and 42.6% in ADA-negative patients, > 0.5 µg/mL or ≤ 0.5 µg/mL at 14 and 52 weeks. respectively (non-significant). www.scandjrheumatol.dk IFX conc µg/ml 348 F Siljehult et al Table 2. Characteristics of patients who terminated treatment before week 52. Side effects* Poor response Characteristics (n = 8) (n = 11) Female, n (%) 6 (75) 10 (91) Disease duration (years), median (IQR) 17.0 (17.5) 20.0 (28.0) Dose (mg), median (IQR) 200 (100) 200 (50) Dose (mg/kg), median (IQR) 3.25 (0.58) 3.23 (1.10) DAS28 at last infusion, median (IQR) 5.2 (4.23) 5.2 (1.1) Average therapy length (weeks), median (IQR) 26 (8) 22 (16) DMARDs, n (%) 8 (100) 11 (100) Glucocorticoids, n (%) 4 (50) 5 (45) Anti-drug antibodies, n (%) 1 (12.5) 2 (18.1) *Severe infections (n = 2), urticaria (n = 4), elevation of alanine transaminase and aspartate transaminase (n = 1), and blurred vision (n = 1) between 14 and 32 weeks. IQR, interquartile range; DAS28, Disease Activity Score based on 28-joint count; DMARDs, disease-modifying anti-rheumatic drugs (methotrexate, sulfasalazine, leflunomide, azathioprine, and cyclosporine). Early-terminating patients phenomenon, which makes it more difficult to evaluate the results (14). The method used in our study of analys- Nineteen patients terminated IFX treatment early, 11 of ing ADAs on plates coated with TNF-α has been eval- them owing to a lack of efficacy between 14 and uated in other studies (9, 13, 14), although the 32 weeks (Table 2). Their DAS28 score at the time of frequencies of ADAs were higher, 55–61% in patients the latest infusion was 5.2 ± 0.6 (mean ± sd), compared with Crohn’s disease (9, 14). This method of analysing with 5.2 ± 1.6 at baseline. Eight patients ended treatment ADAs is used today for routine clinical analyses in because of side effects of IFX treatment, two of whom Sweden. The cut-off value for measuring ADAs in this were positive for ADAs (Table 2). study was set at an IFX concentration ≤ 0.5 µg/mL. Measuring ADAs at a higher concentration of IFX could yield false-positive results since IFX interferes in Discussion the test (17). When analysing patients with RA, there is The loss of clinical response or increased frequency of also a possibility of interference due to RF in RA side effects in patients with RA treated with IFX has patients leading to falsely elevated results in immunoas- been suggested to be due to immunogenicity of the drug says, and also by using bridging ELISAs with IFX- (6, 15, 16). In this study, in which 94 patients with RA coated wells, which was not observed using the method were consecutively included, the concentrations of IFX in this study (9, 22). However, in this study there were and ADAs were evaluated in relation to their response to no differences in frequencies of ADAs irrespective of treatment after 14 and 52 weeks. The frequency of RF status in patients with low concentrations of ADA. A ADAs was fairly low, at 11.7% (11/94), compared limitation of the method used in this study is that ADAs with previous studies reporting frequencies of 26–43% can only be detected in samples with undetectable IFX (4, 7, 17–19), and even up to 54% (5). However, a few levels owing to interference with the method. Of those studies report similar frequencies (8, 20, 21), including a individuals with an IFX concentration ≤ 0.5 µg/mL, only 2017 publication with a frequency of 17% (20). Analys- seven of 16 were ADA positive at 14 weeks and eight of ing samples for the presence of anti-IFX antibodies 26 at 30/52 weeks, with a similar distribution of RF using radioimmunoassays yielded generally higher fre- positivity in each group. quencies, with a few exceptions, compared with ELISAs In this study, 23.4% of patients (18/77) had an IFX with TNF-α-coated plates or functional cell-based repor- concentration ≤ 0.5 µg/mL at 30 or 52 weeks without ter gene assays (RGAs) (4, 7, 21). In a comparative being ADA positive, which is comparable to the fre- study on different assays for analysing IFX concentra- quency reported by van den Bemt et al (19) of almost tion and ADAs, the ELISA and RGA methods showed 30% of patients with low IFX concentrations without fairly similar frequencies, while the sensitivity for ADAs ADAs. We found that these patients were significantly using a radioimmunoassay or homogeneous mobility more often non-responders, implying that they would shift assay was much higher. This suggests that these not benefit from treatment with IFX. The presence of last two methods detect not only drug-neutralizing anti- ADAs was clearly related to a lack of response and bodies but also those that form immune complexes with remission, and therefore ADA positivity was signifi- circulating IFX (21). Furthermore, it has been suggested cantly related to higher DAS28 and also CRP. In gen- that the presence of ADAs may be a transient eral, a lower serum trough concentration of IFX www.scandjrheumatol.dk Infliximab and antidrug antibodies in RA 349 correlated significantly with higher DAS28, ESR, and Disclosure statement CRP, as observed by others (7, 23), and values poten- No potential conflict of interest was reported by the authors. tially resulting from the presence of ADAs. There was a clear relationship between the concentration References of IFX and the response to treatment, as has been shown in 1. Neovius M, Simard JF, Askling J. Nationwide prevalence of rheu- several other studies (6, 18). This relationship was unaf- matoid arthritis and penetration of disease-modifying drugs in fected by BMI or smoking. The results of this study sug- Sweden. Ann Rheum Dis 2011;70:624–9. gest that patients who fail to respond to IFX treatment 2. Silman AJ. Epidemiology of rheumatoid arthritis. 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Journal
Scandinavian Journal of Rheumatology
– Taylor & Francis
Published: Sep 3, 2018
