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Associations between certolizumab pegol serum levels, anti-drug antibodies and treatment response in patients with inflammatory joint diseases: data from the NOR-DMARD study

Associations between certolizumab pegol serum levels, anti-drug antibodies and treatment response... Objectives: To identify a therapeutic target interval for certolizumab pegol drug levels and examine the influence of anti-drug antibodies in patients with inflammatory joint diseases. Methods: Certolizumab pegol and anti-drug antibody levels were measured in serum samples collected after 3 months of certolizumab pegol treatment in 268 patients with inflammatory joint diseases (116 axial spondyloarthritis, 91 rheumatoid arthritis and 61 psoriatic arthritis) in the NOR-DMARD study. Treatment response was defined by Ankylosing Spondylitis Disease Activity Score Clinically important improvement in axial spondyloarthritis, European League Against Rheumatism good/moderate response in rheumatoid arthritis, and improvement in 28-joint Disease Activity Score of ≥ 0.6 in PsA. Serum drug levels and anti-drug antibodies were analysed using automated in-house assays. Results: Certolizumab pegol serum levels varied considerably between individuals (median (IQR) 32.9 (17.3–43.9) mg/L). Certolizumab pegol level ≥ 20 mg/L was associated with treatment response for the total inflammatory joint disease population, with odds ratio (OR) 2.3 (95% CI 1.2–4.5, P = 0.01) and OR 1.9 (95% CI 1.0–3.5, P = 0.05) after 3 and 6 months of treatment, respectively. For individual diagnoses, this association was most consistent for axial spondyloarthritis, with OR 3.4 (95% CI 1.0–11.1, P < 0.05) and OR 3.3 (95% CI 1.0–10.8, P < 0.05), respectively. Certolizumab pegol level > 40 mg/L was not associated with any additional benefit for any of the diagnoses. Anti- drug antibodies were detected in 6.1% (19/310) of samples and were associated with low certolizumab pegol levels (P < 0.01). Conclusions: Serum certolizumab pegol levels 20–40 mg/L were associated with treatment response in inflammatory joint diseases. Our study is the first to show this association in axial spondyloarthritis and psoriatic arthritis patients. The results suggest a possible benefit of therapeutic drug monitoring in patients with inflammatory joint disease on certolizumab pegol treatment. Trial registration: NCT01581294, April 2012. Keywords: TNF-inhibitors, Certolizumab pegol, Serum drug levels, Anti-drug antibodies, Inflammatory joint diseases, Axial spondyloarthritis, Rheumatoid arthritis, Psoriatic arthritis * Correspondence: [email protected] Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Nydalen, Box 4953, 0424 Oslo, Norway Faculty of Medicine, University of Oslo, Oslo, Norway Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 2 of 10 Introduction month follow-up visit. Clinical assessments are per- Tumour necrosis factor alpha inhibitors (TNFi), such as formed at baseline, 3, 6, 9 and 12 months and every 6 certolizumab pegol (CZP), have substantially improved months thereafter. the management of inflammatory joint diseases (IJD). In the current study, we included NOR-DMARD pa- However, a significant proportion of patients do not re- tients enrolled in the registry from January 2013 to De- spond adequately to treatment [1–4]. Low drug levels cember 2016 with a clinical diagnosis of axial and development of anti-drug antibodies (ADAb) have spondyloarthritis (axSpA) (n = 116), RA (n = 91), psori- previously been shown to be associated with lack of re- atic arthritis (PsA) (n = 61) and other IJD (n = 42) start- sponse to TNFi [5–10]. ing treatment with CZP and with available biobank Therapeutic drug monitoring (TDM) can help clini- samples at the 3-month follow-up visit. Serum samples cians tailor treatment with biologic drugs. TDM has the were non-trough, collected at the 3-month visit and potential to reduce under- and overtreatment and has stored in a biobank freezer at − 80 °C. Clinical data from been suggested to improve effectiveness, safety and cost- baseline, 3- and 6-month follow-up visits were used. effectiveness of treatment with biologic drugs. For TDM Patients with axSpA, RA and PsA with available base- to be validated as a clinical tool, therapeutic intervals line disease activity score were included in response ana- must be identified. Previous reports suggest therapeutic lyses (n = 245; 110 axSpA, 81 RA, 54 PsA). Complete intervals in patients treated with infliximab [5, 6, 11, 12] data for the 6-month follow-up visit were available in and adalimumab [7, 8, 13]. Measurement of serum levels 60% (150/252) of patients. An additional 38% (95/252) has become common clinical practice in many rheuma- became eligible for the 6-month response analyses when tology, gastroenterology and dermatology centres for carrying forward their 3-month values. For missing 3- these drugs across Europe. Knowledge on optimal serum month data (n = 24), values from 6 months were carried drug levels of other TNFi, such as CZP, is largely lack- backwards. For patients with available data on some of ing. In addition, the majority of data on serum drug con- the composite score values (n = 3 at 3 months and n =3 centrations in rheumatic diseases are on patients with at 6 months), only the missing components were im- rheumatoid arthritis (RA) only. puted. For those with all components missing, the dis- CZP is a PEGylated humanised Fab’ fragment of a re- ease activity scores themselves were imputed (n =24 at combinant monoclonal murine antibody against TNFα. 3 months and n = 92 at 6 months). Seven patients were Though CZP is extensively used in treatment of IJD, excluded from analyses due to inadequate 3- and 6- knowledge about the optimal serum drug level is limited. month data and unknown reason for discontinuation. An association between CZP levels and treatment re- One patient had non-response imputed because of dis- sponse has previously been shown in a prospective ob- continuation due to lack of efficacy before the 3-month servational study of patients with RA [10]. visit. It is well known that a considerable proportion of pa- tients develop ADAb to infliximab and adalimumab, Clinical response often leading to low drug levels and treatment failure [8, Clinical data for the analyses were collected at the 3- 9, 14–17]. Knowledge about the incidence and clinical and 6-month follow-up visit. Disease activity was relevance of ADAb to CZP is very limited. Jani et al. de- assessed by Ankylosing Spondylitis Disease Activity tected ADAb in 37% of RA patients, and the presence of Score-C-reactive protein (ASDAS-CRP) for axSpA [19] ADAb was significantly associated with lower drug and 28-joint Disease Activity Score-erythrocyte sedimen- levels, but not with clinical outcomes [10]. tation rate (DAS28-ESR) [20] for RA and PsA. Treat- The main objective of our study was to examine the ment response was defined by ASDAS Clinically association between serum CZP levels and treatment re- important improvement (CII) (defined by a reduction of sponse in order to identify a therapeutic target interval ≥ 1.1 units in ASDAS-CRP) in axSpA [19], European in patients with IJD. In addition, we wanted to assess the League Against Rheumatism (EULAR) good/moderate frequency and clinical relevance of early ADAb develop- response in RA [21] and DAS28 improvement ≥ 0.6 in ment in patients treated with CZP. PsA [22]. Patients with other IJD were not included in response analyses. Methods The NOR-DMARD registry and patient selection The NOR-DMARD registry is a longitudinal observa- Adverse events tional study including adult patients with IJD starting Adverse events during the first 700 days of treatment, treatment with biologic disease-modifying antirheumatic where a relation to CZP treatment was suspected, were drugs (bDMARDs) [18]. Biobank samples in the NOR- included in analyses. Adverse event severity was classi- DMARD study are collected at baseline and at the 3- fied according to MedDRA [23]. Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 3 of 10 Measurement of CZP levels and ADAb Statistical analyses CZP levels were analysed retrospectively in non-trough For differences in baseline demographics and clinical serum samples collected at 3 months using an in-house, variables between groups, independent samples t-test, European In-Vitro Diagnostic Devices Directive- Mann-Whitney U test or χ tests were used, as appropri- compliant, time-resolved fluorometric assay automated ate. Statistical tests were two-sided with level of signifi- on the AutoDELFIA (PerkinElmer, Waltham, MA, USA) cance set at 0.05. Associations between CZP levels and immunoassay platform. The assay uses human recom- improvement in disease activity score and response were binant TNFα as capture reagent. Active drug binding to assessed by multivariate linear and logistic regression the TNFα solid phase is detected using a europium- (adjusting for age, sex and prior bDMARD use (yes/no)), labelled anti-kappa light chain monoclonal antibody respectively. Statistical analyses were performed using [24]. ADAb was detected by a principal assay measuring IBM SPSS Statistics, Version 25. neutralising ADAb and two confirmational assays. The principal assay is based on the ability of ADAb to inhibit Results binding of europium-labelled drug to a TNFα solid Baseline characteristics phase [24]. The confirmational tests were an antigen- Baseline characteristics are shown in Table 1, stratified bridging test and a 3-step fluorometric assay. Results by low (< 20 mg/L) vs. high (≥ 20 mg/L) CZP level at 3 were defined as positive if the principal assay and at least months. Female gender was associated with CZP level ≥ one confirmational assay were positive. 20 mg/L in RA patients. No significant differences Table 1 Comparison of baseline characteristics across patients with low (< 20 mg/L) vs. high (≥ 20 mg/L) CZP serum level Axial spondyloarthritis All CZP low (< 20 mg/L) CZP high (≥ 20 mg/L) P value (n = 116) (n = 26) (n = 90) Age, years, mean (SD) 42 (12) 43 (11) 41 (12) 0.61 Female, n (%) 54 (47) 14 (54) 40 (44) 0.40 Disease duration, years, median (IQR)* 2.6 (0.6–14.1) 3.6 (1.7–11.7) 2.3 (0.3–14.8) 0.39 ASDAS-CRP, mean (SD) 2.6 (1.0) 2.4 (0.9) 2.7 (1.0) 0.28 HLA-B27 positive, n (%) 87 (75) 17 (65) 70 (81) 0.09 Prior use of biologic DMARD, n (%) 39 (34) 10 (40) 29 (33) 0.54 Concomitant conventional synthetic DMARD, n (%) 22 (19) 2 (8) 20 (22) 0.10 Rheumatoid arthritis All CZP low (< 20 mg/L) CZP high (≥ 20 mg/L) P value (n = 91) (n = 23) (n = 68) Age, years, mean (SD) 54 (14) 54 (16) 54 (14) 0.90 Female, n (%) 72 (79) 13 (57) 59 (87) < 0.05 Disease duration, years, median (IQR)** 10.1 (2.1–18.9) 17.4 (6.8–23.5) 7.4 (2.0–14.9) 0.10 DAS28, mean (SD) 4.0 (1.4) 3.5 (1.1) 4.2 (1.5) 0.08 RF-positive, n (%) 55 (61) 12 (52) 43 (66) 0.23 Anti-CCP positive, n (%) 59 (66) 13 (57) 46 (71) 0.21 Prior use of biologic DMARD, n (%) 44 (48) 14 (64) 30 (45) 0.13 Concomitant conventional synthetic DMARD, n (%) 67 (74) 16 (70) 51 (75) 0.53 Psoriatic arthritis All CZP low (< 20 mg/L) CZP high (≥ 20 mg/L) P value (n = 61) (n = 17) (n = 44) Age, years, mean (SD) 50 (11) 48 (12) 51 (11) 0.45 Female, n (%) 40 (66) 12 (71) 28 (64) 0.61 Disease duration, years, median (IQR)*** 6.6 (1.5–13.2) 5.4 (1.3–13.5) 6.9 (1.6–13.2) 0.76 DAS28, mean (SD) 3.9 (1.3) 3.9 (1.8) 3.9 (1.2) 0.99 Prior use of biologic DMARD, n (%) 30 (49) 10 (59) 20 (47) 0.39 Concomitant conventional synthetic DMARD, n (%) 38 (67) 8 (53) 30 (71) 0.20 Data available in n = *68, **68, ***40 patients CZP certolizumab pegol, ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score-C-reactive protein, DAS28 28-joint Disease Activity Score, RF rheumatoid factor, Anti-CCP anti-cyclic citrullinated peptides, DMARD disease-modifying antirheumatic drug, SD standard deviation, IQR interquartile range Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 4 of 10 between groups were found for other demographic or Association between CZP levels and treatment response clinical data. In order to identify thresholds for drug level concentration-effect curves after 3 months of treatment were made for axSpA, RA and PsA patients (Fig. 2a–c). Distribution of CZP serum levels For all three diagnoses, the curves illustrate that patients CZP serum levels 3 months after treatment initiation with CZP level 20–39.9 mg/L had the largest mean im- showed considerable variation between individuals provement in disease activity from baseline. In the (Fig. 1). For the total IJD population, median (interquar- multivariate analysis, a serum CZP level ≥ 20 mg/L was tile range (IQR)) CZP level was 32.9 (17.3–43.9) mg/L. associated with ASDAS improvement at 3 months (β = Stratified by diagnosis, median (IQR) CZP level was 35.0 0.6, (95% confidence interval (CI) 0.1–2.0), P = 0.01) and (21.3–45.3) mg/L in axSpA patients, 34.7 (17.6–44.6) 6 months (β = 0.6, (95% CI 0.2–1.1), P < 0.01) in axSpA mg/L in RA and 31.0 (13.6–39.9) mg/L in PsA. In the patients. In RA patients, serum CZP level ≥ 20 mg/L was total population, 17 patients (5.5%) had CZP levels < 1 associated with greater improvement in DAS28 at 3 mg/L, 30 patients (9.7%) had serum levels 1–9.9 mg/L, months (β = 0.9 (95% CI 0.0–1.7), P = 0.04). Further, the 35 (11.3%) 10–19.9 mg/L, 55 (17.7%) 20–29.9 mg/L, 71 association between CZP level ≥ 20 mg/L and DAS28 (22.9%) 30–39.9 mg/L and 102 (32.9%) ≥ 40 mg/L. Data improvement at 6 months was borderline significant for the administered dose of CZP were available in 95% (β = 0.8 (95% CI − 0.1–1.8), P = 0.08). In PsA patients, of patients at 3 months. The majority of patients, 85%, there was a trend for CZP level ≥ 20 mg/L to be associ- were on standard dose, 200 mg every second week at 3 ated with greater improvement in DAS28 at 3 and 6 months. Among patients who were not on standard months; however, it did not reach statistical significance dose, 24 received 200 mg with a longer dosing interval, (β = 0.5 (95% CI − 0.2–1.3), P = 0.14, and β = 0.4 (95% CI 17 received a higher dose (either by shorter interval be- − 0.3–1.1), P = 0.28). tween injections or higher dose) and 1 patient had dis- Furthermore, the associations between serum drug continued treatment before 3 months. All patients were levels and response to treatment, defined as ASDAS CII given the standard loading dose of 400 mg at weeks 0, 2 in axSpA, EULAR good/moderate response in RA, and and 4. DAS28 improvement ≥ 0.6 in PsA were examined. The proportions of responders after 3 and 6 months, for the total IJD population and for axSpA, RA and PsA separ- ately, stratified by the CZP serum level at 3 months, are shown in Table 2 and Fig. 3a, b and Fig. 4a–c. Odds ra- tio (OR) (95% CI) for response in patients with CZP level ≥ 20 mg/L, versus < 20 mg/L, after 3 and 6 months of treatment are also shown in Table 2. Having a serum CZP level ≥ 20 mg/L was associated with response at 3 and 6 months for all three diagnoses combined (OR 2.3 (95% CI 1.2–4.5, P = 0.01), OR 1.9 (95% CI 1.0–3.5, P = 0.05), respectively). However, CZP levels ≥ 40 mg/L were not associated with any additional benefit, and response rates were, on the contrary, lower across all diagnoses. Association between CZP levels and adverse events In the total IJD population, 69 patients had registered one or more infections (the majority had one (n = 42) or two (n = 20) infections). All infections were mild or moderate in severity. With patients stratified by CZP levels < 20, 20–39.9 and ≥ 40 mg/L, the proportions of patients who had ≥ 1 infection were 21%, 22% and 24%, respectively, and the proportions of patients who had ≥ 2 infections were 7%, 8% and 11%, respectively. While there is a slight trend towards more infections with higher drug levels, the dif- Fig. 1 Distribution of certolizumab serum levels (total inflammatory ferences were not statistically significant. Only three pa- joint disease population) at 3 months, mg/L. Median (IQR) tients had ≥ 5 infections, and all these patients had CZP 32.9 (17.3–43.9) levels ≥ 40 mg/L. Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 5 of 10 Fig. 2 Improvement in disease activity from baseline (unadjusted means (95% CI)) at 3 months by certolizumab pegol level: a ASDAS-CRP improvement in axial spondyloarthritis. b DAS28 improvement in rheumatoid arthritis. c DAS28 improvement in psoriatic arthritis. ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score-C-reactive protein; DAS28, 28-joint Disease Activity Score A total of 111 patients had one or more “other” ad- IJD). ADAb-positive patients had significantly lower CZP verse events, most commonly one (n = 74) or two (n = levels than ADAb-negative patients, i.e., median (IQR) 1.0 28). There was one severe allergic skin reaction, while (0.2–6.8) vs. 34.4 (21.2–44.7) mg/L (P <0.01). ADAb was the remaining adverse events were mild or moderate in detected in 53% (9/17) of those with CZP < 1 mg/L, com- severity. The proportion of patients with ≥ 1 and ≥ 2 pared to 3% (10/293) of those with CZP ≥1mg/L. “other” adverse events did not differ between groups Response data were available for 245 patients. Of stratified by CZP levels. these, only 1 out of 11 (9%) ADAb-positive patients was classified as a responder at 3 months. Among ADAb- Frequency and clinical significance of ADAb at 3 months negative patients with response data, 129/234 (55%) sampling were responders. After 3 months of treatment, 19 of 310 (6.1%) patients Among RA patients, 4 of 5 (80%) ADAb-positive pa- were ADAb positive (6 axSpA, 5 RA, 4 PsA and 4 other tients used concomitant synthetic DMARDs (mostly Table 2 Response*(%) at 3 and 6 months, stratified by certolizumab pegol level at 3 months Overall CZP < 20 mg/L CZP 20–39.9 mg/L CZP ≥ 40 mg/L OR** (95% CI) P** Responders* after 3 months All patients (n = 245) 53% 35% 65% 49% 2.3 (1.2–4.5) < 0.05 axSpA (n = 110) 40% 18% 53% 37% 3.4 (1.0–11.1) < 0.05 RA (n = 81) 61% 44% 74% 55% 1.5 (0.5–5.1) 0.48 PsA (n = 54) 69% 47% 77% 77% 4.3 (1.0–17.9) < 0.05 Responders* after 6 months All patients (n = 245) 52% 38% 63% 48% 1.9 (1.0–3.5) 0.05 axSpA (n = 110) 40% 18% 55% 34% 3.3 (1.0–10.8) < 0.05 RA (n = 81) 57% 50% 62% 55% 1.1 (0.3–3.4) 0.92 PsA (n = 54) 70% 53% 77% 70% 3.3 (0.8–13.3) 0.09 CZP certolizumab pegol, OR odds ratio, CI confidence interval *Response in axial spondyloarthritis (axSpA) was defined by clinically important improvement the Ankylosing Spondylitis Disease Activity Score, in rheumatoid arthritis (RA) as European League Against Rheumatism good/moderate response, and in psoriatic arthritis (PsA) as improvement of ≥ 0.6 in 28-joint Disease Activity Score **Multivariate logistic regression comparing response in patients with CZP < 20 vs ≥ 20 mg/L, adjusting for age, sex and prior biologic disease-modifying antirheumatic drug use (yes/no) Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 6 of 10 Fig. 3 Proportion of responders (total inflammatory joint disease population) at a 3 months and b 6 months, stratified by certolizumab level (mg/ L) at 3 months. Response in axial spondyloarthritis was defined by Clinically important improvement the Ankylosing Spondylitis Disease Activity Score, in rheumatoid arthritis as European League Against Rheumatism good/moderate response, and in psoriatic arthritis as improvement of ≥ 0.6 in 28-joint Disease Activity Score methotrexate). Numbers for ADAb-negative patients Considerable inter-individual variation in serum CZP were 63 out of 86 (73%). concentrations on the same standard dose was revealed, Eight patients experienced one or more injection-site suggesting both over- and undertreatment. reaction, and all of these were ADAb negative at 3 The association between CZP serum levels and clinical months. response was most consistent for patients with axSpA. Associations between serum drug levels, ADAb and clin- ical effect have been found in patients with ankylosing Discussion spondylitis (AS) for other TNFi [14, 25–27]; however, it Our study is, to our knowledge, the first to demonstrate has been difficult to establish a clear therapeutic target a concentration-effect curve in CZP-treated patients interval in this patient group [28, 29]. The high number with axSpA and PsA. Furthermore, we confirm the of patients with axSpA and their relatively short median concentration-effect relationship previously demon- disease duration compared to other studies are among strated in RA [10]. the strengths of our study. In PsA patients, data Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 7 of 10 Fig. 4 Proportion of responders at 3 months, stratified by certolizumab level (mg/L). a ASDAS CII responders in axial spondyloarthritis. b EULAR good/moderate response in rheumatoid arthritis. c DAS28 improvement ≥ 0.6 in psoriatic arthritis. ASDAS CII, Clinically important improvement the Ankylosing Spondylitis Disease Activity Score; EULAR good/moderate, European League Against Rheumatism good/moderate response; DAS28 improvement ≥ 0.6, improvement of ≥ 0.6 in 28-joint Disease Activity Score describing associations between serum level of TNFi and explorative concentration-effect analyses (depicted in response are currently limited, and this study is the first Figs. 2, 3 and 4) and were further evaluated by regres- to suggest a therapeutic target level for CZP in PsA. In sion analyses. The suggested target of 20 mg/L is com- RA patients, data showing a concentration-effect rela- parable to previous results from a study of RA patients tionship for CZP have previously been published by Jani [10] and reports in Crohn’s patients, where CZP levels ≥ et al. [10]. In our study, the association between CZP 23.3 mg/L and ≥ 14.8 at weeks 10 and 12, respectively, level and DAS28 improvement was statistically signifi- have been shown to be associated with better outcomes cant in RA patients, while the association between CZP [30, 31]. However, results in Crohn’s patients may not level and EULAR response was not. This discrepancy be comparable to results in patients with rheumatic might be due to lack of statistical power to show an as- diagnoses, as intestinal loss of serum proteins (including sociation to a dichotomous response measure, in antibody-based drugs) during periods of high disease ac- addition to the large group of RA patients with CZP tivity is a major confounder in inflammatory bowel levels ≥ 40 mg/L, in which the proportion of responders diseases. was relatively low. We were not able to identify statistically significant as- The magnitude of p values obtained in the statistical sociations between CZP levels and adverse events (in- analyses is related to the number of patients with the in- cluding infections). However, a high number of dividual diagnoses in this study. We believe this vari- infections (> 5) were only seen in patients with high CZP ation can likely be explained by the lower number of levels. A previous study on RA patients, including but patients with RA and PsA compared to axSpA, rather not specifically assessing CZP, has demonstrated an as- than a true difference between the diagnoses. Our study sociation between high serum levels of biologic drugs was not powered to study individual diagnoses, but we and risk of infection [32]. In our study, the number of considered it relevant to examine whether there were reported injection-site reactions was too small to con- obvious differences between individual diagnoses. clude regarding an association with ADAb. We aimed to identify cut-off values applicable to clin- Disease activity measures and response criteria are de- ical use. The thresholds for drug levels were based on fined differently in axSpA, RA and PsA, which could Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 8 of 10 affect interpretation and comparability of results. Due to et al. have shown that non-responders to a TNFi in the lack of more extensive joint counts and PsA-specific presence of detectable serum drug trough levels and no measures, we measured disease activity and response by detectable ADAb had higher probability of achieving re- DAS28 in PsA patients for this study. Sensitivity analyses sponse by switching to a drug with different mode of ac- using a modified Disease Activity index for Psoriatic tion, rather than to another TNFi [39]. As a result of the Arthritis, using 28 and 32 swollen/tender joint counts relatively short time from patients receiving the standard (DAPSA28 and DAPSA32) [33–35], were performed in loading dose to the collection of biobank samples in our PsA (data not shown). These analyses showed the same study, some patients might not have reached steady- trends as analyses using DAS28, though the levels of sig- state drug levels. However, we do not believe this is a nificance declined. We believe this is a consequence of major contributor when biobank samples were collected the lower proportion of respondents among PsA pa- after 3 months of treatment. tients, especially in the ≥ 40 mg/L group, when using In total, ADAb against CZP were detected in 6.1% of DAPSA28/-32 improvement ≥ 50% as a response meas- patients after 3 months of treatment. We found that ure, compared to DAS28 response. Results were similar early development of ADAb was associated with low when using DAPSA28 compared to DAPSA32. PsA is a drug levels and reduced treatment response, albeit the heterogeneous disease with diverse manifestations, mak- number of ADAb-positive patients was relatively small. ing disease activity measures a challenging and contro- Our data are not able to demonstrate a protective effect versial issue. However, DAS28 is frequently used in PsA, of concomitant synthetic DMARDs on ADAb formation and DAPSA28 has been shown to be useful in the ab- in RA patients, but the number of ADAb-positive RA sence of more extensive joint counts [33]. Results from patients was too small to conclude. Phase III-IV studies this cohort are quite similar across diagnoses. We there- have shown a similar frequency (5.0–8.1%) of ADAb in fore believe it is possible to suggest a common thera- RA patients [1, 2, 40, 41]. Jani et al. found ADAb in 37% peutic target level. of patients in non-trough serum samples in RA patients Serum drug levels in the present study are non-trough. by 12 months using a sensitive radioimmunoassay [10]. Measurement of trough levels is inconvenient in clinical Studies assessing ADAb frequency are not necessarily practice for CZP and other TNFi that are self- comparable, because of differences in patient selection, administered. Hence, it is useful to identify a therapeutic study design and methods used to measure ADAb. For range for non-trough serum samples. Previous data indi- this study, we chose a confirmational strategy for ADAb cate that pharmacologic testing with non-trough levels is detection because knowledge is limited about the im- clinically useful in TNFi-treated patients [10, 36]. In munogenicity of PEGylated Fab’ fragments. Further, high addition, it has been suggested by pharmacokinetic concentrations of CZP in samples may interfere in simulation that intra-individual variation between injec- ADAb assays. Admittedly, the frequency of ADAb in our tions is quite small for subcutaneously dosed TNFi, i.e., study could be underestimated because ADAb was mea- adalimumab and etanercept, in RA patients [37]. Adali- sured in non-trough samples. A possible reason for a mumab levels have also been shown to be similar in very low drug level (< 1 mg/L) in the absence of ADAb, samples from different time points during an injection which was found in 8 patients, could be lack of cycle in Crohn’s disease [38]. compliance. A substantial number of patients had CZP levels above We were able to identify a common therapeutic target 40 mg/L, and the proportion of responders was lower in interval for CZP across patients with different IJD. Es- the ≥ 40 mg/L group than in the 20–39.9 mg/L group for tablishment of a therapeutic target interval is necessary all three diagnoses. While this finding might be counter- for further validation of TDM as a clinical tool to im- intuitive, it is in agreement with what has previously prove efficacy of treatment with CZP. The consistent as- been shown for DAS28 improvement in RA patients sociation between serum level and effect supports a [10]. Non-responders with high CZP levels might repre- benefit of personalised dosing by TDM in patients on sent a subset of patients with a low TNFα load in their CZP treatment, as do the considerable variability in disease, leading to reduced binding of CZP and large serum levels among patients on standard dose CZP, in- amounts of unbound drug. As with most assays used for dicating both over- and undertreatment. Biobank sam- detection of biologic drugs, our assay only measures ac- ples were collected at the first visit following treatment tive drug still able to bind its target. These patients initiation, which we believe is a strength of this study. could most likely receive lower dosing without increas- Tools to aid treatment decisions shortly after initiation ing the risk of disease worsening, which would reduce of treatment are needed when using the treat-to-target costs and potentially also the risk of side effects. More strategy recommended by EULAR and EULAR-ASAS in importantly, these patients might benefit from switching early disease management [42–44]. The lack of data on to a biologic drug with another mode of action. Garcês body weight and of more extensive joint counts in PsA Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 9 of 10 patients (discussed above) is a limitation of our study. Consent for publication Not applicable. These parameters are not recorded in the NOR- DMARD registry. In conclusion, our results demonstrate that CZP Competing interests JG Roche; GLG Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, serum levels vary considerably between patients with IJD Novartis, Pfizer, MSD, Roche; UCB and SWS Roche; EKS Pfizer; TKK AbbVie, on standard dose. Serum levels ≥ 20 mg/L were associ- Biogen, Celltrion, Egis, Eli Lilly, Hospira, MSD, Mylan, Novartis, Oktal, Orion ated with treatment response. However, having CZP Pharma, Pfizer, Roche, Sandoz, Sanofi; UCB, BMS and NB Pfizer, Orion Pharma, Napp pharmaceuticals, Takeda, Roche, Janssen, Novartis. level > 40 mg/L was not associated with any additional The remaining authors declare that they have no competing interests. benefit. Results were comparable between diagnoses. Disclosures listed above include fees for speaking and/or consulting or ADAb against CZP were associated with low drug levels research funding to the institution (Diakonhjemmet Hospital). and reduced treatment response. These results suggest Author details that a therapeutic interval of 20–40 mg/L can be imple- Department of Medical Biochemistry, Oslo University Hospital, mented in clinical practice for non-trough serum sam- Radiumhospitalet, Nydalen, Box 4953, 0424 Oslo, Norway. Faculty of Medicine, University of Oslo, Oslo, Norway. Department of Rheumatology, ples in patients with IJD, but the clinical significance of Diakonhjemmet Hospital, Oslo, Norway. Lillehammer Hospital for Rheumatic tailoring TNFi treatment in IJD by TDM should be fur- Diseases, Lillehammer, Norway. ther explored in randomised controlled clinical strategy Received: 21 May 2019 Accepted: 23 September 2019 trials. Abbreviations ADAb: Anti-drug antibody/-ies; Anti-CCP: Anti-cyclic citrullinated peptides; References AS: Ankylosing spondylitis; ASDAS-CRP: Ankylosing Spondylitis Disease 1. Keystone E, Heijde D, Mason D Jr, Landewe R, Vollenhoven RV, Combe B, Activity Score-C-reactive protein; axSpA: Axial spondyloarthritis; et al. Certolizumab pegol plus methotrexate is significantly more effective bDMARDs: Biologic disease-modifying antirheumatic drugs; CI: Confidence than placebo plus methotrexate in active rheumatoid arthritis: findings of a interval; CII: Clinically important improvement; CZP: Certolizumab pegol; fifty-two-week, phase III, multicenter, randomized, double-blind, placebo- DAS28-ESR: 28-joint Disease Activity Score-erythrocyte sedimentation rate; controlled, parallel-group study. Arthritis Rheum. 2008;58(11):3319–29. DMARD: Disease-modifying antirheumatic drug; EULAR: European League 2. Smolen J, Landewe RB, Mease P, Brzezicki J, Mason D, Luijtens K, et al. Against Rheumatism; IQR: Interquartile range; IJD: Inflammatory joint Efficacy and safety of certolizumab pegol plus methotrexate in active diseases; OR: Odds ratio; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis; rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann RF: Rheumatoid factor; SD: Standard deviation; TNFi: Tumour necrosis factor Rheum Dis. 2009;68(6):797–804. alpha inhibitors; TDM: Therapeutic drug monitoring 3. Mease P, Deodhar A, Fleischmann R, Wollenhaupt J, Gladman D, Leszczynski P, et al. Effect of certolizumab pegol over 96 weeks in patients with Acknowledgements psoriatic arthritis with and without prior antitumour necrosis factor We thank the patients for participating in this study and the local exposure. RMD open. 2015;1(1):e000119. rheumatology staff for data collection. We thank the Department of 4. van der Heijde D, Dougados M, Landewe R, Sieper J, Maksymowych WP, Rheumatology at Diakonhjemmet Hospital, Lillehammer Hospital for Rudwaleit M, et al. Sustained efficacy, safety and patient-reported outcomes Rheumatic Diseases and Vestre Viken Hospital Trust for collection of biobank of certolizumab pegol in axial spondyloarthritis: 4-year outcomes from samples. We thank Inge-Christoffer Olsen for help with data extraction and RAPID-axSpA. Rheumatology (Oxford). 2017;56(9):1498–509. valuable input regarding statistical analyses. In addition, we thank Rolf Anton 5. St Clair EW, Wagner CL, Fasanmade AA, Wang B, Schaible T, Kavanaugh A, Klaasen for help with table design and Trine Bjøro for valuable input in et al. The relationship of serum infliximab concentrations to clinical manuscript preparation and facilitation during the study. This manuscript is improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, based on work previously presented at EULAR 2018 and ACR 2018. randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002; 46(6):1451–9. Authors’ contributions 6. Wolbink GJ, Voskuyl AE, Lems WF, de Groot E, Nurmohamed MT, Tak PP, TKK, EL, NB, GLG and JG contributed to the study design. EL, TKK, GLG, SWS et al. Relationship between serum trough infliximab levels, pretreatment C and EKS contributed to the data acquisition: clinical data. DJW, NB and JG reactive protein levels, and clinical response to infliximab treatment in contributed to the laboratory data. JG, JS, EL, SWS, GLG and NB contributed patients with rheumatoid arthritis. Ann Rheum Dis. 2005;64(5):704–7. to the data analysis. JG, NB, SWS, GLG, DJW, EL, JS and TKK contributed to 7. Pouw MF, Krieckaert CL, Nurmohamed MT, van der Kleij D, Aarden L, the manuscript preparation. All authors have read and approved the final Rispens T, et al. Key findings towards optimising adalimumab treatment: the manuscript. concentration-effect curve. Ann Rheum Dis. 2015;74(3):513–8. 8. van Kuijk AW, de Groot M, Stapel SO, Dijkmans BA, Wolbink GJ, Tak PP. Relationship between the clinical response to adalimumab treatment and Funding serum levels of adalimumab and anti-adalimumab antibodies in patients The NOR-DMARD registry has been financially supported by pharmaceutical with psoriatic arthritis. Ann Rheum Dis. 2010;69(3):624–5. companies, but the sponsors had no influence on study design, analyses and 9. Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF presentation of data. therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. 2013;72(12):1947–55. Availability of data and materials 10. Jani M, Isaacs JD, Morgan AW, Wilson AG, Plant D, Hyrich KL, et al. The datasets used and analysed during the current study are available from High frequency of antidrug antibodies and association of random drug the corresponding author on reasonable request. levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort. Ann Rheum Dis. Ethics approval and consent to participate 2017;76(1):208–13. The study was approved by the Regional Ethics Committee of Eastern 11. Takeuchi T, Miyasaka N, Inoue K, Abe T, Koike T. Impact of trough serum Norway ref. 2011/1339, the Norwegian Medicines Agency and the level on radiographic and clinical response to infliximab plus methotrexate Norwegian Data Inspectorate. All patients provided written, informed in patients with rheumatoid arthritis: results from the RISING study. Mod consent before inclusion. Rheumatol. 2009;19(5):478–87. Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 10 of 10 12. 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Kneepkens EL, Wei JC, Nurmohamed MT, Yeo KJ, Chen CY, van der Horst- assessed by a modified Disease Activity index for PSoriatic Arthritis (DAPSA) Bruinsma IE, et al. Immunogenicity, adalimumab levels and clinical response based on 28 joints? Ann Rheum Dis. 2018;77(12):1736–41. in ankylosing spondylitis patients during 24 weeks of follow-up. Ann Rheum 34. Schoels MM, Aletaha D, Alasti F, Smolen JS. Disease activity in psoriatic Dis. 2015;74(2):396–401. arthritis (PsA): defining remission and treatment success using the DAPSA 15. van Schouwenburg PA, Rispens T, Wolbink GJ. Immunogenicity of anti-TNF score. Ann Rheum Dis. 2016;75(5):811–8. biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol. 2013;9(3): 35. Michelsen B, Kristianslund EK, Hammer HB, Fagerli KM, Lie E, Wierod A, et al. 164–72. Discordance between tender and swollen joint count as well as patient's 16. Mok CC, van der Kleij D, Wolbink GJ. 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Arthritis Rheumatol. 2015;67(8):2011–9. management: implementation of data capture from electronic health 37. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor records. Clin Exp Rheumatol. 2014;32(5 Suppl 85):S-158–62. antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 19. Machado P, Landewe R, Lie E, Kvien TK, Braun J, Baker D, et al. Ankylosing 2008;117(2):244–79. spondylitis disease activity score (ASDAS): defining cut-off values for disease 38. Ungar B, Engel T, Yablecovitch D, Lahat A, Lang A, Avidan B, et al. activity states and improvement scores. Ann Rheum Dis. 2011;70(1):47–53. Prospective observational evaluation of time-dependency of adalimumab 20. Prevoo ML. Van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, immunogenicity and drug concentrations: the poetic study. Am J van Riel PL. Modified disease activity scores that include twenty-eight-joint Gastroenterol. 2018;113(6):890–8. counts. 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Clin Exp Rheumatol. 2010;28(5):661–8. 978-91. 26. de Vries MK, Wolbink GJ, Stapel SO, de Vrieze H, van Denderen JC, Dijkmans 44. Gossec L, Smolen JS, Ramiro S, de Wit M, Cutolo M, Dougados M, et al. BA, et al. Decreased clinical response to infliximab in ankylosing spondylitis European league against rheumatism (EULAR) recommendations for the is correlated with anti-infliximab formation. Ann Rheum Dis. 2007;66(9): management of psoriatic arthritis with pharmacological therapies: 2015 1252–4. update. Ann Rheum Dis. 2016;75(3):499–510. 27. Kneepkens EL, Krieckaert CL, van der Kleij D, Nurmohamed MT, van der Horst-Bruinsma IE, Rispens T, et al. Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of Publisher’sNote follow-up. Ann Rheum Dis. 2015;74(10):1825–9. 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Associations between certolizumab pegol serum levels, anti-drug antibodies and treatment response in patients with inflammatory joint diseases: data from the NOR-DMARD study

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Medicine & Public Health; Rheumatology; Orthopedics
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Abstract

Objectives: To identify a therapeutic target interval for certolizumab pegol drug levels and examine the influence of anti-drug antibodies in patients with inflammatory joint diseases. Methods: Certolizumab pegol and anti-drug antibody levels were measured in serum samples collected after 3 months of certolizumab pegol treatment in 268 patients with inflammatory joint diseases (116 axial spondyloarthritis, 91 rheumatoid arthritis and 61 psoriatic arthritis) in the NOR-DMARD study. Treatment response was defined by Ankylosing Spondylitis Disease Activity Score Clinically important improvement in axial spondyloarthritis, European League Against Rheumatism good/moderate response in rheumatoid arthritis, and improvement in 28-joint Disease Activity Score of ≥ 0.6 in PsA. Serum drug levels and anti-drug antibodies were analysed using automated in-house assays. Results: Certolizumab pegol serum levels varied considerably between individuals (median (IQR) 32.9 (17.3–43.9) mg/L). Certolizumab pegol level ≥ 20 mg/L was associated with treatment response for the total inflammatory joint disease population, with odds ratio (OR) 2.3 (95% CI 1.2–4.5, P = 0.01) and OR 1.9 (95% CI 1.0–3.5, P = 0.05) after 3 and 6 months of treatment, respectively. For individual diagnoses, this association was most consistent for axial spondyloarthritis, with OR 3.4 (95% CI 1.0–11.1, P < 0.05) and OR 3.3 (95% CI 1.0–10.8, P < 0.05), respectively. Certolizumab pegol level > 40 mg/L was not associated with any additional benefit for any of the diagnoses. Anti- drug antibodies were detected in 6.1% (19/310) of samples and were associated with low certolizumab pegol levels (P < 0.01). Conclusions: Serum certolizumab pegol levels 20–40 mg/L were associated with treatment response in inflammatory joint diseases. Our study is the first to show this association in axial spondyloarthritis and psoriatic arthritis patients. The results suggest a possible benefit of therapeutic drug monitoring in patients with inflammatory joint disease on certolizumab pegol treatment. Trial registration: NCT01581294, April 2012. Keywords: TNF-inhibitors, Certolizumab pegol, Serum drug levels, Anti-drug antibodies, Inflammatory joint diseases, Axial spondyloarthritis, Rheumatoid arthritis, Psoriatic arthritis * Correspondence: [email protected] Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Nydalen, Box 4953, 0424 Oslo, Norway Faculty of Medicine, University of Oslo, Oslo, Norway Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 2 of 10 Introduction month follow-up visit. Clinical assessments are per- Tumour necrosis factor alpha inhibitors (TNFi), such as formed at baseline, 3, 6, 9 and 12 months and every 6 certolizumab pegol (CZP), have substantially improved months thereafter. the management of inflammatory joint diseases (IJD). In the current study, we included NOR-DMARD pa- However, a significant proportion of patients do not re- tients enrolled in the registry from January 2013 to De- spond adequately to treatment [1–4]. Low drug levels cember 2016 with a clinical diagnosis of axial and development of anti-drug antibodies (ADAb) have spondyloarthritis (axSpA) (n = 116), RA (n = 91), psori- previously been shown to be associated with lack of re- atic arthritis (PsA) (n = 61) and other IJD (n = 42) start- sponse to TNFi [5–10]. ing treatment with CZP and with available biobank Therapeutic drug monitoring (TDM) can help clini- samples at the 3-month follow-up visit. Serum samples cians tailor treatment with biologic drugs. TDM has the were non-trough, collected at the 3-month visit and potential to reduce under- and overtreatment and has stored in a biobank freezer at − 80 °C. Clinical data from been suggested to improve effectiveness, safety and cost- baseline, 3- and 6-month follow-up visits were used. effectiveness of treatment with biologic drugs. For TDM Patients with axSpA, RA and PsA with available base- to be validated as a clinical tool, therapeutic intervals line disease activity score were included in response ana- must be identified. Previous reports suggest therapeutic lyses (n = 245; 110 axSpA, 81 RA, 54 PsA). Complete intervals in patients treated with infliximab [5, 6, 11, 12] data for the 6-month follow-up visit were available in and adalimumab [7, 8, 13]. Measurement of serum levels 60% (150/252) of patients. An additional 38% (95/252) has become common clinical practice in many rheuma- became eligible for the 6-month response analyses when tology, gastroenterology and dermatology centres for carrying forward their 3-month values. For missing 3- these drugs across Europe. Knowledge on optimal serum month data (n = 24), values from 6 months were carried drug levels of other TNFi, such as CZP, is largely lack- backwards. For patients with available data on some of ing. In addition, the majority of data on serum drug con- the composite score values (n = 3 at 3 months and n =3 centrations in rheumatic diseases are on patients with at 6 months), only the missing components were im- rheumatoid arthritis (RA) only. puted. For those with all components missing, the dis- CZP is a PEGylated humanised Fab’ fragment of a re- ease activity scores themselves were imputed (n =24 at combinant monoclonal murine antibody against TNFα. 3 months and n = 92 at 6 months). Seven patients were Though CZP is extensively used in treatment of IJD, excluded from analyses due to inadequate 3- and 6- knowledge about the optimal serum drug level is limited. month data and unknown reason for discontinuation. An association between CZP levels and treatment re- One patient had non-response imputed because of dis- sponse has previously been shown in a prospective ob- continuation due to lack of efficacy before the 3-month servational study of patients with RA [10]. visit. It is well known that a considerable proportion of pa- tients develop ADAb to infliximab and adalimumab, Clinical response often leading to low drug levels and treatment failure [8, Clinical data for the analyses were collected at the 3- 9, 14–17]. Knowledge about the incidence and clinical and 6-month follow-up visit. Disease activity was relevance of ADAb to CZP is very limited. Jani et al. de- assessed by Ankylosing Spondylitis Disease Activity tected ADAb in 37% of RA patients, and the presence of Score-C-reactive protein (ASDAS-CRP) for axSpA [19] ADAb was significantly associated with lower drug and 28-joint Disease Activity Score-erythrocyte sedimen- levels, but not with clinical outcomes [10]. tation rate (DAS28-ESR) [20] for RA and PsA. Treat- The main objective of our study was to examine the ment response was defined by ASDAS Clinically association between serum CZP levels and treatment re- important improvement (CII) (defined by a reduction of sponse in order to identify a therapeutic target interval ≥ 1.1 units in ASDAS-CRP) in axSpA [19], European in patients with IJD. In addition, we wanted to assess the League Against Rheumatism (EULAR) good/moderate frequency and clinical relevance of early ADAb develop- response in RA [21] and DAS28 improvement ≥ 0.6 in ment in patients treated with CZP. PsA [22]. Patients with other IJD were not included in response analyses. Methods The NOR-DMARD registry and patient selection The NOR-DMARD registry is a longitudinal observa- Adverse events tional study including adult patients with IJD starting Adverse events during the first 700 days of treatment, treatment with biologic disease-modifying antirheumatic where a relation to CZP treatment was suspected, were drugs (bDMARDs) [18]. Biobank samples in the NOR- included in analyses. Adverse event severity was classi- DMARD study are collected at baseline and at the 3- fied according to MedDRA [23]. Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 3 of 10 Measurement of CZP levels and ADAb Statistical analyses CZP levels were analysed retrospectively in non-trough For differences in baseline demographics and clinical serum samples collected at 3 months using an in-house, variables between groups, independent samples t-test, European In-Vitro Diagnostic Devices Directive- Mann-Whitney U test or χ tests were used, as appropri- compliant, time-resolved fluorometric assay automated ate. Statistical tests were two-sided with level of signifi- on the AutoDELFIA (PerkinElmer, Waltham, MA, USA) cance set at 0.05. Associations between CZP levels and immunoassay platform. The assay uses human recom- improvement in disease activity score and response were binant TNFα as capture reagent. Active drug binding to assessed by multivariate linear and logistic regression the TNFα solid phase is detected using a europium- (adjusting for age, sex and prior bDMARD use (yes/no)), labelled anti-kappa light chain monoclonal antibody respectively. Statistical analyses were performed using [24]. ADAb was detected by a principal assay measuring IBM SPSS Statistics, Version 25. neutralising ADAb and two confirmational assays. The principal assay is based on the ability of ADAb to inhibit Results binding of europium-labelled drug to a TNFα solid Baseline characteristics phase [24]. The confirmational tests were an antigen- Baseline characteristics are shown in Table 1, stratified bridging test and a 3-step fluorometric assay. Results by low (< 20 mg/L) vs. high (≥ 20 mg/L) CZP level at 3 were defined as positive if the principal assay and at least months. Female gender was associated with CZP level ≥ one confirmational assay were positive. 20 mg/L in RA patients. No significant differences Table 1 Comparison of baseline characteristics across patients with low (< 20 mg/L) vs. high (≥ 20 mg/L) CZP serum level Axial spondyloarthritis All CZP low (< 20 mg/L) CZP high (≥ 20 mg/L) P value (n = 116) (n = 26) (n = 90) Age, years, mean (SD) 42 (12) 43 (11) 41 (12) 0.61 Female, n (%) 54 (47) 14 (54) 40 (44) 0.40 Disease duration, years, median (IQR)* 2.6 (0.6–14.1) 3.6 (1.7–11.7) 2.3 (0.3–14.8) 0.39 ASDAS-CRP, mean (SD) 2.6 (1.0) 2.4 (0.9) 2.7 (1.0) 0.28 HLA-B27 positive, n (%) 87 (75) 17 (65) 70 (81) 0.09 Prior use of biologic DMARD, n (%) 39 (34) 10 (40) 29 (33) 0.54 Concomitant conventional synthetic DMARD, n (%) 22 (19) 2 (8) 20 (22) 0.10 Rheumatoid arthritis All CZP low (< 20 mg/L) CZP high (≥ 20 mg/L) P value (n = 91) (n = 23) (n = 68) Age, years, mean (SD) 54 (14) 54 (16) 54 (14) 0.90 Female, n (%) 72 (79) 13 (57) 59 (87) < 0.05 Disease duration, years, median (IQR)** 10.1 (2.1–18.9) 17.4 (6.8–23.5) 7.4 (2.0–14.9) 0.10 DAS28, mean (SD) 4.0 (1.4) 3.5 (1.1) 4.2 (1.5) 0.08 RF-positive, n (%) 55 (61) 12 (52) 43 (66) 0.23 Anti-CCP positive, n (%) 59 (66) 13 (57) 46 (71) 0.21 Prior use of biologic DMARD, n (%) 44 (48) 14 (64) 30 (45) 0.13 Concomitant conventional synthetic DMARD, n (%) 67 (74) 16 (70) 51 (75) 0.53 Psoriatic arthritis All CZP low (< 20 mg/L) CZP high (≥ 20 mg/L) P value (n = 61) (n = 17) (n = 44) Age, years, mean (SD) 50 (11) 48 (12) 51 (11) 0.45 Female, n (%) 40 (66) 12 (71) 28 (64) 0.61 Disease duration, years, median (IQR)*** 6.6 (1.5–13.2) 5.4 (1.3–13.5) 6.9 (1.6–13.2) 0.76 DAS28, mean (SD) 3.9 (1.3) 3.9 (1.8) 3.9 (1.2) 0.99 Prior use of biologic DMARD, n (%) 30 (49) 10 (59) 20 (47) 0.39 Concomitant conventional synthetic DMARD, n (%) 38 (67) 8 (53) 30 (71) 0.20 Data available in n = *68, **68, ***40 patients CZP certolizumab pegol, ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score-C-reactive protein, DAS28 28-joint Disease Activity Score, RF rheumatoid factor, Anti-CCP anti-cyclic citrullinated peptides, DMARD disease-modifying antirheumatic drug, SD standard deviation, IQR interquartile range Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 4 of 10 between groups were found for other demographic or Association between CZP levels and treatment response clinical data. In order to identify thresholds for drug level concentration-effect curves after 3 months of treatment were made for axSpA, RA and PsA patients (Fig. 2a–c). Distribution of CZP serum levels For all three diagnoses, the curves illustrate that patients CZP serum levels 3 months after treatment initiation with CZP level 20–39.9 mg/L had the largest mean im- showed considerable variation between individuals provement in disease activity from baseline. In the (Fig. 1). For the total IJD population, median (interquar- multivariate analysis, a serum CZP level ≥ 20 mg/L was tile range (IQR)) CZP level was 32.9 (17.3–43.9) mg/L. associated with ASDAS improvement at 3 months (β = Stratified by diagnosis, median (IQR) CZP level was 35.0 0.6, (95% confidence interval (CI) 0.1–2.0), P = 0.01) and (21.3–45.3) mg/L in axSpA patients, 34.7 (17.6–44.6) 6 months (β = 0.6, (95% CI 0.2–1.1), P < 0.01) in axSpA mg/L in RA and 31.0 (13.6–39.9) mg/L in PsA. In the patients. In RA patients, serum CZP level ≥ 20 mg/L was total population, 17 patients (5.5%) had CZP levels < 1 associated with greater improvement in DAS28 at 3 mg/L, 30 patients (9.7%) had serum levels 1–9.9 mg/L, months (β = 0.9 (95% CI 0.0–1.7), P = 0.04). Further, the 35 (11.3%) 10–19.9 mg/L, 55 (17.7%) 20–29.9 mg/L, 71 association between CZP level ≥ 20 mg/L and DAS28 (22.9%) 30–39.9 mg/L and 102 (32.9%) ≥ 40 mg/L. Data improvement at 6 months was borderline significant for the administered dose of CZP were available in 95% (β = 0.8 (95% CI − 0.1–1.8), P = 0.08). In PsA patients, of patients at 3 months. The majority of patients, 85%, there was a trend for CZP level ≥ 20 mg/L to be associ- were on standard dose, 200 mg every second week at 3 ated with greater improvement in DAS28 at 3 and 6 months. Among patients who were not on standard months; however, it did not reach statistical significance dose, 24 received 200 mg with a longer dosing interval, (β = 0.5 (95% CI − 0.2–1.3), P = 0.14, and β = 0.4 (95% CI 17 received a higher dose (either by shorter interval be- − 0.3–1.1), P = 0.28). tween injections or higher dose) and 1 patient had dis- Furthermore, the associations between serum drug continued treatment before 3 months. All patients were levels and response to treatment, defined as ASDAS CII given the standard loading dose of 400 mg at weeks 0, 2 in axSpA, EULAR good/moderate response in RA, and and 4. DAS28 improvement ≥ 0.6 in PsA were examined. The proportions of responders after 3 and 6 months, for the total IJD population and for axSpA, RA and PsA separ- ately, stratified by the CZP serum level at 3 months, are shown in Table 2 and Fig. 3a, b and Fig. 4a–c. Odds ra- tio (OR) (95% CI) for response in patients with CZP level ≥ 20 mg/L, versus < 20 mg/L, after 3 and 6 months of treatment are also shown in Table 2. Having a serum CZP level ≥ 20 mg/L was associated with response at 3 and 6 months for all three diagnoses combined (OR 2.3 (95% CI 1.2–4.5, P = 0.01), OR 1.9 (95% CI 1.0–3.5, P = 0.05), respectively). However, CZP levels ≥ 40 mg/L were not associated with any additional benefit, and response rates were, on the contrary, lower across all diagnoses. Association between CZP levels and adverse events In the total IJD population, 69 patients had registered one or more infections (the majority had one (n = 42) or two (n = 20) infections). All infections were mild or moderate in severity. With patients stratified by CZP levels < 20, 20–39.9 and ≥ 40 mg/L, the proportions of patients who had ≥ 1 infection were 21%, 22% and 24%, respectively, and the proportions of patients who had ≥ 2 infections were 7%, 8% and 11%, respectively. While there is a slight trend towards more infections with higher drug levels, the dif- Fig. 1 Distribution of certolizumab serum levels (total inflammatory ferences were not statistically significant. Only three pa- joint disease population) at 3 months, mg/L. Median (IQR) tients had ≥ 5 infections, and all these patients had CZP 32.9 (17.3–43.9) levels ≥ 40 mg/L. Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 5 of 10 Fig. 2 Improvement in disease activity from baseline (unadjusted means (95% CI)) at 3 months by certolizumab pegol level: a ASDAS-CRP improvement in axial spondyloarthritis. b DAS28 improvement in rheumatoid arthritis. c DAS28 improvement in psoriatic arthritis. ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score-C-reactive protein; DAS28, 28-joint Disease Activity Score A total of 111 patients had one or more “other” ad- IJD). ADAb-positive patients had significantly lower CZP verse events, most commonly one (n = 74) or two (n = levels than ADAb-negative patients, i.e., median (IQR) 1.0 28). There was one severe allergic skin reaction, while (0.2–6.8) vs. 34.4 (21.2–44.7) mg/L (P <0.01). ADAb was the remaining adverse events were mild or moderate in detected in 53% (9/17) of those with CZP < 1 mg/L, com- severity. The proportion of patients with ≥ 1 and ≥ 2 pared to 3% (10/293) of those with CZP ≥1mg/L. “other” adverse events did not differ between groups Response data were available for 245 patients. Of stratified by CZP levels. these, only 1 out of 11 (9%) ADAb-positive patients was classified as a responder at 3 months. Among ADAb- Frequency and clinical significance of ADAb at 3 months negative patients with response data, 129/234 (55%) sampling were responders. After 3 months of treatment, 19 of 310 (6.1%) patients Among RA patients, 4 of 5 (80%) ADAb-positive pa- were ADAb positive (6 axSpA, 5 RA, 4 PsA and 4 other tients used concomitant synthetic DMARDs (mostly Table 2 Response*(%) at 3 and 6 months, stratified by certolizumab pegol level at 3 months Overall CZP < 20 mg/L CZP 20–39.9 mg/L CZP ≥ 40 mg/L OR** (95% CI) P** Responders* after 3 months All patients (n = 245) 53% 35% 65% 49% 2.3 (1.2–4.5) < 0.05 axSpA (n = 110) 40% 18% 53% 37% 3.4 (1.0–11.1) < 0.05 RA (n = 81) 61% 44% 74% 55% 1.5 (0.5–5.1) 0.48 PsA (n = 54) 69% 47% 77% 77% 4.3 (1.0–17.9) < 0.05 Responders* after 6 months All patients (n = 245) 52% 38% 63% 48% 1.9 (1.0–3.5) 0.05 axSpA (n = 110) 40% 18% 55% 34% 3.3 (1.0–10.8) < 0.05 RA (n = 81) 57% 50% 62% 55% 1.1 (0.3–3.4) 0.92 PsA (n = 54) 70% 53% 77% 70% 3.3 (0.8–13.3) 0.09 CZP certolizumab pegol, OR odds ratio, CI confidence interval *Response in axial spondyloarthritis (axSpA) was defined by clinically important improvement the Ankylosing Spondylitis Disease Activity Score, in rheumatoid arthritis (RA) as European League Against Rheumatism good/moderate response, and in psoriatic arthritis (PsA) as improvement of ≥ 0.6 in 28-joint Disease Activity Score **Multivariate logistic regression comparing response in patients with CZP < 20 vs ≥ 20 mg/L, adjusting for age, sex and prior biologic disease-modifying antirheumatic drug use (yes/no) Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 6 of 10 Fig. 3 Proportion of responders (total inflammatory joint disease population) at a 3 months and b 6 months, stratified by certolizumab level (mg/ L) at 3 months. Response in axial spondyloarthritis was defined by Clinically important improvement the Ankylosing Spondylitis Disease Activity Score, in rheumatoid arthritis as European League Against Rheumatism good/moderate response, and in psoriatic arthritis as improvement of ≥ 0.6 in 28-joint Disease Activity Score methotrexate). Numbers for ADAb-negative patients Considerable inter-individual variation in serum CZP were 63 out of 86 (73%). concentrations on the same standard dose was revealed, Eight patients experienced one or more injection-site suggesting both over- and undertreatment. reaction, and all of these were ADAb negative at 3 The association between CZP serum levels and clinical months. response was most consistent for patients with axSpA. Associations between serum drug levels, ADAb and clin- ical effect have been found in patients with ankylosing Discussion spondylitis (AS) for other TNFi [14, 25–27]; however, it Our study is, to our knowledge, the first to demonstrate has been difficult to establish a clear therapeutic target a concentration-effect curve in CZP-treated patients interval in this patient group [28, 29]. The high number with axSpA and PsA. Furthermore, we confirm the of patients with axSpA and their relatively short median concentration-effect relationship previously demon- disease duration compared to other studies are among strated in RA [10]. the strengths of our study. In PsA patients, data Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 7 of 10 Fig. 4 Proportion of responders at 3 months, stratified by certolizumab level (mg/L). a ASDAS CII responders in axial spondyloarthritis. b EULAR good/moderate response in rheumatoid arthritis. c DAS28 improvement ≥ 0.6 in psoriatic arthritis. ASDAS CII, Clinically important improvement the Ankylosing Spondylitis Disease Activity Score; EULAR good/moderate, European League Against Rheumatism good/moderate response; DAS28 improvement ≥ 0.6, improvement of ≥ 0.6 in 28-joint Disease Activity Score describing associations between serum level of TNFi and explorative concentration-effect analyses (depicted in response are currently limited, and this study is the first Figs. 2, 3 and 4) and were further evaluated by regres- to suggest a therapeutic target level for CZP in PsA. In sion analyses. The suggested target of 20 mg/L is com- RA patients, data showing a concentration-effect rela- parable to previous results from a study of RA patients tionship for CZP have previously been published by Jani [10] and reports in Crohn’s patients, where CZP levels ≥ et al. [10]. In our study, the association between CZP 23.3 mg/L and ≥ 14.8 at weeks 10 and 12, respectively, level and DAS28 improvement was statistically signifi- have been shown to be associated with better outcomes cant in RA patients, while the association between CZP [30, 31]. However, results in Crohn’s patients may not level and EULAR response was not. This discrepancy be comparable to results in patients with rheumatic might be due to lack of statistical power to show an as- diagnoses, as intestinal loss of serum proteins (including sociation to a dichotomous response measure, in antibody-based drugs) during periods of high disease ac- addition to the large group of RA patients with CZP tivity is a major confounder in inflammatory bowel levels ≥ 40 mg/L, in which the proportion of responders diseases. was relatively low. We were not able to identify statistically significant as- The magnitude of p values obtained in the statistical sociations between CZP levels and adverse events (in- analyses is related to the number of patients with the in- cluding infections). However, a high number of dividual diagnoses in this study. We believe this vari- infections (> 5) were only seen in patients with high CZP ation can likely be explained by the lower number of levels. A previous study on RA patients, including but patients with RA and PsA compared to axSpA, rather not specifically assessing CZP, has demonstrated an as- than a true difference between the diagnoses. Our study sociation between high serum levels of biologic drugs was not powered to study individual diagnoses, but we and risk of infection [32]. In our study, the number of considered it relevant to examine whether there were reported injection-site reactions was too small to con- obvious differences between individual diagnoses. clude regarding an association with ADAb. We aimed to identify cut-off values applicable to clin- Disease activity measures and response criteria are de- ical use. The thresholds for drug levels were based on fined differently in axSpA, RA and PsA, which could Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 8 of 10 affect interpretation and comparability of results. Due to et al. have shown that non-responders to a TNFi in the lack of more extensive joint counts and PsA-specific presence of detectable serum drug trough levels and no measures, we measured disease activity and response by detectable ADAb had higher probability of achieving re- DAS28 in PsA patients for this study. Sensitivity analyses sponse by switching to a drug with different mode of ac- using a modified Disease Activity index for Psoriatic tion, rather than to another TNFi [39]. As a result of the Arthritis, using 28 and 32 swollen/tender joint counts relatively short time from patients receiving the standard (DAPSA28 and DAPSA32) [33–35], were performed in loading dose to the collection of biobank samples in our PsA (data not shown). These analyses showed the same study, some patients might not have reached steady- trends as analyses using DAS28, though the levels of sig- state drug levels. However, we do not believe this is a nificance declined. We believe this is a consequence of major contributor when biobank samples were collected the lower proportion of respondents among PsA pa- after 3 months of treatment. tients, especially in the ≥ 40 mg/L group, when using In total, ADAb against CZP were detected in 6.1% of DAPSA28/-32 improvement ≥ 50% as a response meas- patients after 3 months of treatment. We found that ure, compared to DAS28 response. Results were similar early development of ADAb was associated with low when using DAPSA28 compared to DAPSA32. PsA is a drug levels and reduced treatment response, albeit the heterogeneous disease with diverse manifestations, mak- number of ADAb-positive patients was relatively small. ing disease activity measures a challenging and contro- Our data are not able to demonstrate a protective effect versial issue. However, DAS28 is frequently used in PsA, of concomitant synthetic DMARDs on ADAb formation and DAPSA28 has been shown to be useful in the ab- in RA patients, but the number of ADAb-positive RA sence of more extensive joint counts [33]. Results from patients was too small to conclude. Phase III-IV studies this cohort are quite similar across diagnoses. We there- have shown a similar frequency (5.0–8.1%) of ADAb in fore believe it is possible to suggest a common thera- RA patients [1, 2, 40, 41]. Jani et al. found ADAb in 37% peutic target level. of patients in non-trough serum samples in RA patients Serum drug levels in the present study are non-trough. by 12 months using a sensitive radioimmunoassay [10]. Measurement of trough levels is inconvenient in clinical Studies assessing ADAb frequency are not necessarily practice for CZP and other TNFi that are self- comparable, because of differences in patient selection, administered. Hence, it is useful to identify a therapeutic study design and methods used to measure ADAb. For range for non-trough serum samples. Previous data indi- this study, we chose a confirmational strategy for ADAb cate that pharmacologic testing with non-trough levels is detection because knowledge is limited about the im- clinically useful in TNFi-treated patients [10, 36]. In munogenicity of PEGylated Fab’ fragments. Further, high addition, it has been suggested by pharmacokinetic concentrations of CZP in samples may interfere in simulation that intra-individual variation between injec- ADAb assays. Admittedly, the frequency of ADAb in our tions is quite small for subcutaneously dosed TNFi, i.e., study could be underestimated because ADAb was mea- adalimumab and etanercept, in RA patients [37]. Adali- sured in non-trough samples. A possible reason for a mumab levels have also been shown to be similar in very low drug level (< 1 mg/L) in the absence of ADAb, samples from different time points during an injection which was found in 8 patients, could be lack of cycle in Crohn’s disease [38]. compliance. A substantial number of patients had CZP levels above We were able to identify a common therapeutic target 40 mg/L, and the proportion of responders was lower in interval for CZP across patients with different IJD. Es- the ≥ 40 mg/L group than in the 20–39.9 mg/L group for tablishment of a therapeutic target interval is necessary all three diagnoses. While this finding might be counter- for further validation of TDM as a clinical tool to im- intuitive, it is in agreement with what has previously prove efficacy of treatment with CZP. The consistent as- been shown for DAS28 improvement in RA patients sociation between serum level and effect supports a [10]. Non-responders with high CZP levels might repre- benefit of personalised dosing by TDM in patients on sent a subset of patients with a low TNFα load in their CZP treatment, as do the considerable variability in disease, leading to reduced binding of CZP and large serum levels among patients on standard dose CZP, in- amounts of unbound drug. As with most assays used for dicating both over- and undertreatment. Biobank sam- detection of biologic drugs, our assay only measures ac- ples were collected at the first visit following treatment tive drug still able to bind its target. These patients initiation, which we believe is a strength of this study. could most likely receive lower dosing without increas- Tools to aid treatment decisions shortly after initiation ing the risk of disease worsening, which would reduce of treatment are needed when using the treat-to-target costs and potentially also the risk of side effects. More strategy recommended by EULAR and EULAR-ASAS in importantly, these patients might benefit from switching early disease management [42–44]. The lack of data on to a biologic drug with another mode of action. Garcês body weight and of more extensive joint counts in PsA Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 9 of 10 patients (discussed above) is a limitation of our study. Consent for publication Not applicable. These parameters are not recorded in the NOR- DMARD registry. In conclusion, our results demonstrate that CZP Competing interests JG Roche; GLG Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, serum levels vary considerably between patients with IJD Novartis, Pfizer, MSD, Roche; UCB and SWS Roche; EKS Pfizer; TKK AbbVie, on standard dose. Serum levels ≥ 20 mg/L were associ- Biogen, Celltrion, Egis, Eli Lilly, Hospira, MSD, Mylan, Novartis, Oktal, Orion ated with treatment response. However, having CZP Pharma, Pfizer, Roche, Sandoz, Sanofi; UCB, BMS and NB Pfizer, Orion Pharma, Napp pharmaceuticals, Takeda, Roche, Janssen, Novartis. level > 40 mg/L was not associated with any additional The remaining authors declare that they have no competing interests. benefit. Results were comparable between diagnoses. Disclosures listed above include fees for speaking and/or consulting or ADAb against CZP were associated with low drug levels research funding to the institution (Diakonhjemmet Hospital). and reduced treatment response. These results suggest Author details that a therapeutic interval of 20–40 mg/L can be imple- Department of Medical Biochemistry, Oslo University Hospital, mented in clinical practice for non-trough serum sam- Radiumhospitalet, Nydalen, Box 4953, 0424 Oslo, Norway. Faculty of Medicine, University of Oslo, Oslo, Norway. Department of Rheumatology, ples in patients with IJD, but the clinical significance of Diakonhjemmet Hospital, Oslo, Norway. Lillehammer Hospital for Rheumatic tailoring TNFi treatment in IJD by TDM should be fur- Diseases, Lillehammer, Norway. ther explored in randomised controlled clinical strategy Received: 21 May 2019 Accepted: 23 September 2019 trials. Abbreviations ADAb: Anti-drug antibody/-ies; Anti-CCP: Anti-cyclic citrullinated peptides; References AS: Ankylosing spondylitis; ASDAS-CRP: Ankylosing Spondylitis Disease 1. Keystone E, Heijde D, Mason D Jr, Landewe R, Vollenhoven RV, Combe B, Activity Score-C-reactive protein; axSpA: Axial spondyloarthritis; et al. Certolizumab pegol plus methotrexate is significantly more effective bDMARDs: Biologic disease-modifying antirheumatic drugs; CI: Confidence than placebo plus methotrexate in active rheumatoid arthritis: findings of a interval; CII: Clinically important improvement; CZP: Certolizumab pegol; fifty-two-week, phase III, multicenter, randomized, double-blind, placebo- DAS28-ESR: 28-joint Disease Activity Score-erythrocyte sedimentation rate; controlled, parallel-group study. Arthritis Rheum. 2008;58(11):3319–29. DMARD: Disease-modifying antirheumatic drug; EULAR: European League 2. Smolen J, Landewe RB, Mease P, Brzezicki J, Mason D, Luijtens K, et al. Against Rheumatism; IQR: Interquartile range; IJD: Inflammatory joint Efficacy and safety of certolizumab pegol plus methotrexate in active diseases; OR: Odds ratio; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis; rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann RF: Rheumatoid factor; SD: Standard deviation; TNFi: Tumour necrosis factor Rheum Dis. 2009;68(6):797–804. alpha inhibitors; TDM: Therapeutic drug monitoring 3. Mease P, Deodhar A, Fleischmann R, Wollenhaupt J, Gladman D, Leszczynski P, et al. Effect of certolizumab pegol over 96 weeks in patients with Acknowledgements psoriatic arthritis with and without prior antitumour necrosis factor We thank the patients for participating in this study and the local exposure. RMD open. 2015;1(1):e000119. rheumatology staff for data collection. We thank the Department of 4. van der Heijde D, Dougados M, Landewe R, Sieper J, Maksymowych WP, Rheumatology at Diakonhjemmet Hospital, Lillehammer Hospital for Rudwaleit M, et al. Sustained efficacy, safety and patient-reported outcomes Rheumatic Diseases and Vestre Viken Hospital Trust for collection of biobank of certolizumab pegol in axial spondyloarthritis: 4-year outcomes from samples. We thank Inge-Christoffer Olsen for help with data extraction and RAPID-axSpA. Rheumatology (Oxford). 2017;56(9):1498–509. valuable input regarding statistical analyses. In addition, we thank Rolf Anton 5. St Clair EW, Wagner CL, Fasanmade AA, Wang B, Schaible T, Kavanaugh A, Klaasen for help with table design and Trine Bjøro for valuable input in et al. The relationship of serum infliximab concentrations to clinical manuscript preparation and facilitation during the study. This manuscript is improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, based on work previously presented at EULAR 2018 and ACR 2018. randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002; 46(6):1451–9. Authors’ contributions 6. Wolbink GJ, Voskuyl AE, Lems WF, de Groot E, Nurmohamed MT, Tak PP, TKK, EL, NB, GLG and JG contributed to the study design. EL, TKK, GLG, SWS et al. Relationship between serum trough infliximab levels, pretreatment C and EKS contributed to the data acquisition: clinical data. DJW, NB and JG reactive protein levels, and clinical response to infliximab treatment in contributed to the laboratory data. JG, JS, EL, SWS, GLG and NB contributed patients with rheumatoid arthritis. Ann Rheum Dis. 2005;64(5):704–7. to the data analysis. JG, NB, SWS, GLG, DJW, EL, JS and TKK contributed to 7. Pouw MF, Krieckaert CL, Nurmohamed MT, van der Kleij D, Aarden L, the manuscript preparation. All authors have read and approved the final Rispens T, et al. Key findings towards optimising adalimumab treatment: the manuscript. concentration-effect curve. Ann Rheum Dis. 2015;74(3):513–8. 8. van Kuijk AW, de Groot M, Stapel SO, Dijkmans BA, Wolbink GJ, Tak PP. Relationship between the clinical response to adalimumab treatment and Funding serum levels of adalimumab and anti-adalimumab antibodies in patients The NOR-DMARD registry has been financially supported by pharmaceutical with psoriatic arthritis. Ann Rheum Dis. 2010;69(3):624–5. companies, but the sponsors had no influence on study design, analyses and 9. Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF presentation of data. therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. 2013;72(12):1947–55. Availability of data and materials 10. Jani M, Isaacs JD, Morgan AW, Wilson AG, Plant D, Hyrich KL, et al. The datasets used and analysed during the current study are available from High frequency of antidrug antibodies and association of random drug the corresponding author on reasonable request. levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort. Ann Rheum Dis. Ethics approval and consent to participate 2017;76(1):208–13. The study was approved by the Regional Ethics Committee of Eastern 11. Takeuchi T, Miyasaka N, Inoue K, Abe T, Koike T. Impact of trough serum Norway ref. 2011/1339, the Norwegian Medicines Agency and the level on radiographic and clinical response to infliximab plus methotrexate Norwegian Data Inspectorate. All patients provided written, informed in patients with rheumatoid arthritis: results from the RISING study. Mod consent before inclusion. Rheumatol. 2009;19(5):478–87. Gehin et al. Arthritis Research & Therapy (2019) 21:256 Page 10 of 10 12. 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