Abstract

Background

Development of anti-drug-antibodies (ADAb) to biological drugs can lead to low serum drug levels, reduced drug survival, loss of therapeutic response, and adverse events, such as infusion reactions. Immunogenicity of biological therapies has been studied extensively in rheumatoid arthritis (RA), but clearly less is known about the role of immunogenicity in the treatment of patients with spondyloarthritis (SpA) and ankylosing spondylitis (AS). In some studies, the development of ADAb has resulted in reduced efficacy, whereas in other studies no correlation between the presence of ADAb and disease activity has been observed. Anti-infliximab antibodies have been observed in 15–29% of AS patients [1] and SpA patients [2–4]. Development of anti-infliximab antibodies was associated with higher disease activity, lower infliximab trough levels and higher rate of infusion related reactions [1, 3, 4]. Anti-adalimumab antibodies have been observed in approximately 30% of AS and axSpA patients, and they have been associated with lower or undetectable serum drug levels and lower rate of response [5–7]. However, no association between ADAb against adalimumab and the disease activity was observed in patients with peripheral SpA [8], AS [9] or, according to a meta-analysis, AS or other SpA [10]. Immunogenicity of etanercept is negligible in SpA [11, 12] and AS patients [13]. Immunogenicity of golimumab has been reported to be low in patients with AS [14, 15] and SpA [16], and the presence of antibodies against golimumab has not been associated with lower clinical response [15, 16]. Prevalence of anti-certolizumab pegol ADAb has been reported to be low in patients with SpA [17] but relatively high in RA patients [18].

In addition to the presence of ADAb, also low drug trough level has been shown to result in lower clinical response in RA [19–24], but it is not clear whether this is true also in SpA.

Concomitant use of conventional synthetic disease-modifying antirheumatic drugs (csDMARD) has been shown to reduce the immunogenicity of biological drugs in RA, Crohn’s disease, or juvenile idiopathic arthritis patients using infliximab or adalimumab [25, 26]. Furthermore, concomitant use of csDMARD leads to better response in RA patients treated with tumor necrosis factor (TNF) inhibitors [27]. According to the recent international guidelines, csDMARD are not recommended for the treatment of axial SpA [28]. However, in practice, sulfasalazine (SASP) or methotrexate (MTX) are often used as monotherapy or in combination with biological DMARD. It is not known whether MTX can prevent the formation of ADAb in patients with SpA and the evidence of the benefit of concomitant use of csDMARD in SpA is somewhat conflicting [3, 4, 7, 28–33].

The aim of this study was to determine the extent and significance of immunization to anti-TNF drugs in real-life setting in unselected SpA patients with axial disease, and to assess the contribution of factors such as body mass index (BMI) and concomitant use of csDMARD on the immunogenicity.

Materials and methods

Results

Characteristics of the patient cohort

Of the 313 patients who gave their consent to the study, 273 gave a blood sample, and were included into the study. Of these patients 180 (66%) were male, 99 (36%) used adalimumab, 83 (30%) etanercept, 79 (29%) golimumab, and 12 (4%) certolizumab pegol. Of the patients 157 (58%) were using their first biologic drug, and of them 72% were male. The first biologic drug was used by 56 (57%) of the patients in adalimumab group, 50 (60%) in etanercept group, 43 (54%) in golimumab group and 8 (67%) in certolizumab pegol group. The characteristics of the patient cohort are presented in Table ​Table11.

Table 1

Characteristics of the patient cohort

	Adalimumab N=99	Etanercept N=83	Golimumab N=79	Certolizumab pegol N=12	p value
Number of men, n (%)	60 (61)	53 (64)	59 (75)	8 (67)	0.25
Age, mean (SD)	46 (11)	44 (12)	42 (11)	47 (13)	0.12
BMI	26.1 (4.6)	26.2 (4.5)	26.8 (4.7)	25.6 (3.9)	0.74
Disease duration (years), mean (SD)	15.8 (10.3)	14.8 (10.1)	10.9 (9.4)	8.8 (6.9)	<0.001
BASDAI, mean (SD)	1.7 (1.8)	2.1 (1.8)	2.0 (1.7)	1.2 (1.2)	0.12
MASES, mean (SD)	0.4 (1.4)	0.4 (1.4)	0.4 (1.3)	0.1 (0.3)	0.057
BASFI, mean (SD)	1.5 (2.0)	2.0 (2.0)	1.6 (1.5)	1.2 (1.0)	0.24
ESR, mean (SD)	8 (8)	9 (9)	6 (6)	5 (6)	0.064
CRP, mean (SD)	3 (4)	4 (5)	3 (3)	3 (4)	0.53
HLA-B27, n (%)	87 (94)	74 (95)	69 (90)	12 (100)	0.58
Treatment duration with current medicine (months) median (IQR), range	46 (22.71) [1–126]	46 (18.71) [2–131]	17 (9.33) [2–101]	7 (3.10) [3–23]	<0.001
Duration of all biologic treatment (months), median (IQR), range	57 (35.104) [3, 172]	55 (31.91) [2–177]	25 (16.55) [2–210]	8 (3.60) [3–110]	<0.001
DMARD, n (%)
None	44 (44)	42 (51)	36 (46)	3 (25)	0.40
Methotrexate	41 (41)	25 (30)	32 (41)	6 (50)	0.30
Sulfasalazine	21 (21)	22 (27)	17 (22)	5 (42)	0.39
Leflunomide	1 (1)	0 (0)	0 (0)	0 (0)	0.99
Peroral glucocorticoid, n (%)	5 (5)	2 (2)	3 (4)	3 (25)	0.039
Previous biologic treatment
Number, n (%)					0.69
0	56 (57)	50 (60)	43 (54)	8 (67)
1	36 (36)	24 (29)	21 (27)	2 (17)
2	6 (6)	5 (6)	11 (14)	2 (17)
3–4	1 (1)	4 (5)	4 (5)	0 (0)
Previous biologic treatment
Certolizumab pegol	2 (2)	3 (4)	2 (3)	.
Etanercept	29 (29)	.	17 (22)	1 (8)
Adalimumab	.	25 (30)	22 (28)	2 (17)
Golimumab	5 (5)	7 (8)	.	2 (17)
Infliximab	12 (12)	6 (7)	14 (18)	1 (8)

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BMI body mass index, BASDAI Bath Ankylosing Spondylitis Disease Activity Index, MASES Maastricht Enthesitis Score, BASFI Bath Ankylosing Spondylitis Functional Index, ESR erythrocyte sedimentation rate, CRP C-reactive protein, HLA-B27 human leukocyte antigen B27, DMARD disease-modifying antirheumatic drug

Mean duration of disease was 10 years for those who used their first biologic drug and 15 years for those who had used one or more biologic drugs previously (p<0.001). As expected the mean age was higher in the group who had had prior biologic treatment (47 vs. 43 years, p=0.003). The two groups did not differ with respect to weight, BMI, mean result of Schober’s test, occipital-wall test, or CRP, nor with respect to the use of concomitant csDMARD or glucocorticoid therapy. ESR was lower in those who used their first biologic drug (p=0.015) (data not shown).

Drug trough levels and effect of ADAb on trough levels and TNF-blocking capacity

The mean drug trough concentrations of different TNF inhibitors are presented in Supplementary Table 1. The mean drug trough levels were 8.1 mg/L, 1.6 μg/mL, 1.5 μg/mL and 30.3 μg/mL for adalimumab, etanercept, golimumab and certolizumab, respectively. The mean drug trough concentrations were in the target level in 138 (51%) of the patients. 99 patients (36%) had drug concentration lower than the target level and higher than the target drug concentration was detected in 36% of patients using adalimumab.

The effect of ADAb on drug trough levels in patients using adalimumab is depicted in Fig. 1. At low ADAb concentrations, no clear effect on the drug trough levels could be seen. However, at high ADAb concentrations, decreased drug trough levels are evident, and at the highest ADAb concentration, no measurable drug concentration could be detected.

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Fig. 1

The association of ADAb concentration and the drug trough level in patients using adalimumab. Left, mean drug trough level of those without detectable ADAb. Right; black dots show the individual values of each patient with detected ADAb. The dotted line indicates the suggested therapeutic drug trough level of adalimumab

TNF-blocking capacity reflects the ability of patients’ serum to neutralize TNF before next injection of anti-TNF drug. High TNF-blocking capacity (RGA index) means that the patient’s sera can still neutralize produced TNF. The TNF-blocking capacity of the patients using adalimumab is depicted as a function of drug trough level in Fig. 2. A clear correlation can be seen between the drug trough level of adalimumab and the TNF-blocking capacity of the patient’s serum (r=0.75, 95% CI 0.64–0.82). In patients with high ADAb concentration (>23 AU/mL), the TNF-blocking capacity is low, i.e., the patient’s serum has low or no ability to neutralize TNF. However, the presence of low concentrations of ADAb (<23 AU/mL) did not significantly reduce the TNF-blocking capacity, i.e., many of those patients have significant TNF-blocking capacity left before the next injection of the drug. A clear correlation between the drug trough level and the TNF-blocking capacity could be observed also in case of golimumab (r=0.79, 95% CI 0.77–0.86). Patients with positive ADAb in the golimumab group also had low TNF-blocking capacity (low RGA index). In case of etanercept, there was no clear correlation between drug trough concentration and the TNF-blocking capacity, as good TNF-blocking capacity could be seen also at relatively low drug concentrations.

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Fig. 2

TNF-blocking capacity of adalimumab, golimumab and etanercept. Gray circles (adalimumab) represent patients with low level of ADAb (<23 AU/mL) and black circles patients with high level of ADAb (>23 AU/mL). In golimumab users, black circles represent patients who are positive for ADAb

Low drug trough level but not the presence of anti-drug antibodies associates with high disease activity

Significant association was found between low drug trough concentration and high ESR (p=0.032) and high MASES value (p=0.007) in the entire population. Low drug concentration was associated with high MASES also when patients using adalimumab were studied separately (r=− 0.23 (CI − 0.41 to – 0.03), p=0.023). Also the RGA index correlated with MASES; r=− 0.25 (CI − 0.43 to − 0.05), p=0.014. However, no significant correlation was found between drug trough level and BASDAI or between the presence of ADAb and BASDAI. In patients using any anti-TNF drug there was no statistically significant correlation between the presence of ADAb and BASDAI (r=− 0.18 (95% CI − 0.36 to 0.02), p=0.080), BASFI (r=− 0.13 (95% CI − 0.32 to 0.07), p=0.21), or MASES (r=0.18 (95% CI − 0.02 to 0.36), p=0.081). Figure 3 shows the BASDAI values in ADAb-negative and ADAb-positive adalimumab users. This reveals that many patients with no ADAb had very high BASDAI values and the number of patients with high level of ADAb was rather low, thus possibly explaining the lack of correlation between ADAb and BASDAI.

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Fig. 3

BASDAI values of AS patients using adalimumab. Left, the mean BASDAI values of patients with no ADAb. Right: The black dots show individual BASDAI values of ADAb-positive patients as a function of ADAb concentration

Discussion

In this study, we show that significant proportion of SpA patients using subcutaneous anti-TNF drugs have developed ADAb against the drug they are using. The significance of immunization to biological drugs is not clear in SpA. Bornstein et al. found out that ADAb were detected in 15% of 39 SpA patients (4/14 on infliximab and 2/16 on adalimumab), of which all had undetectable drug trough levels. ADAb positivity was also associated with higher disease activity [12]. In another study on axSpA patients 27.5% of patients had anti-adalimumab antibodies. ADAb were associated with lower drug levels and higher clinical activity evaluated by BASDAI and ASDAS [40]. In a recent study by Ducourau et al., ADAb were detected in 36.4% of axSpA patients using adalimumab. Also in this study immunization was associated with lower drug levels and higher clinical activity [7]. These results are concordant with the previously published data showing that most ADAb against adalimumab are neutralizing [41]. In the present study, 11% of all users of subcutaneous anti-TNF drugs had developed ADAb. As in RA, the highest rate of immunization was observed in patients who used adalimumab (21%). This is in agreement with previous studies demonstrating ADAb against adalimumab in about 30% of RA [42] and AS patients [5–7, 43]. It seems that as in the earlier mentioned studies the anti-adalimumab antibodies were neutralizing since all the patients with very low drug trough level were ADAb positive [44]. We did not detect ADAb against etanercept, which is also in agreement with previous studies with patients with SpA [11, 12], AS [13, 43], and RA [23]. Of the patients using golimumab, 3% had ADAb, also in agreement with previous studies [14–16]. A total of 50% of certolizumab pegol users were positive for ADAb. However, most of those had drug trough level at the target level, and therefore, the antibodies may not be neutralizing, and thus the clinical significance of the ADAb remains unclear. The number of patients in certolizumab pegol group was also only 12, and therefore no definite conclusions can be made. In earlier studies, the rate of immunization has been lower in axSpA patients, and anti-certolizumab antibodies have been associated with lower drug levels yet the clinical significance remaining unclear [17, 45]. The number of biologic drugs used earlier did not correlate with immunization.

Patients with concomitant MTX had less frequently ADAb, as compared to those not using MTX, suggesting a protective effect of MTX on immunization also in patients with SpA. In contrast, SASP did not show protective effect against immunization. Higher BMI and longer duration of the disease correlated with the presence of ADAb, and younger age and long duration of biologic treatment correlated negatively with ADAb positivity in adalimumab users.

Lower adalimumab concentrations as well as lower clinical response has been observed in AS or axSpA patients with BMI>30, as compared to those with BMI<25 [46–48]. Theoretically, the lower adalimumab serum levels due to changes in volume distribution could predispose obese patients to immunization against adalimumab. However, in spite of the lower serum drug levels, no difference was observed in rate of immunization [46]. Obesity has been associated with lower TNF inhibitor levels also in RA patients [23] and lower clinical response in patients with rheumatic diseases using TNF inhibitors [49]. In the present study, higher BMI correlated with lower drug trough concentration. Higher BMI also correlated with ADAb positivity in adalimumab users.

The presence of ADAb correlated negatively with drug trough concentration in all the treatment groups in which ADAb were detected (adalimumab, golimumab, and certolizumab pegol). However, the presence of ADAb did not significantly correlate with disease activity. This is most likely explained by the fact that low levels of ADAb did not have significant effect on drug trough levels. As shown in Fig. 2 patients with low levels of ADAb had significant remaining TNF-blocking capacity, and only in those with high levels of ADAb the TNF-blocking capacity was low. As this study was cross-sectional, it is impossible to know whether the patients with low level of ADAb later developed higher ADAb levels or lost their treatment response. Low drug trough levels were associated with higher disease activity, as reflected by the association with higher ESR and higher MASES.

A correlation was observed between adalimumab and golimumab drug trough level and the TNF-blocking capacity expressed as RGA index. In case of etanercept, no clear correlation could be observed between the TNF-blocking capacity and the drug trough level, as the TNF-blocking capacity was good also at lower drug concentrations. The reason for this is not clear. Also, in earlier studies, the clinical relevance of drug level of etanercept seems to be somewhat controversial in patients with both AS [13, 50] and RA [23, 51].

Based on these results, we believe that measuring drug concentration and ADAb in SpA patients using TNF inhibitors with the exception of etanercept is useful both in patients with active disease, but also in those patients who seem to respond to therapy to avoid unnecessary treatment in those who have been immunized to the drug and have therefore unmeasurable drug levels. This is supported by a recent study by Pedersen et al. who showed that therapeutic drug monitoring of TNF inhibitors leads to better clinical response and cost management in the treatment of patients with rheumatic diseases [52]. A recent review concluded that measuring drug levels and ADAb in RA and SpA patients with biologic treatment might be useful both in case of poor response and longer clinical remission [53].

The study has several limitations. The aim of the study was to evaluate the extent and significance of immunization in unselected patients coming to regular outpatient visit. Our study is a cross-sectional study, and thus it does not allow the analysis of the kinetics of immunization to TNF alpha inhibitors or allow the follow up of the patients. Although the study population is relatively large the subgroups of patients using certolizumab pegol and ADAb-positive group of patients using golimumab are rather small, which makes it difficult to draw conclusions concerning immunization and its clinical relevance in these subgroups of patients.

Conclusion

A significant proportion of patients had been immunized to the subcutaneous anti-TNF drug they were using. The presence of ADAb was associated with lower drug concentration and reduced TNF-blocking capacity. Low drug trough levels correlated with higher ESR and MASES. The use of MTX reduced the risk for immunization in patients with SpA, whereas SASP did not. There was no clear correlation between ADAb and the BASDAI, BASFI or MASES scores, likely because the low ADAb levels had no significant effect on TNF-blocking capacity. Thus the significance of finding of low ADAb level in patients is not clear. It is likely that patients with high drug antibody levels and low drug trough concentrations do not benefit from the drug they are using. Thus, measuring of drug trough level and ADAb may be useful to optimize treatment individually and achieve better cost management.

Supplementary Information

Acknowledgements

Author contributions

JH: writing—original draft, writing—review and editing; PP: investigation; TS: investigation, writing—review and editing; TL: investigation; PI: investigation; OK-S: investigation, writing—review and editing; RP: investigation, writing—review and editing; TU: investigation; LP: investigation; KT: investigation; MJK: investigation, writing—review and editing; TY-K: investigation; RT: investigation; HR: investigation; SK: investigation; KP: investigation; JA: investigation; PE: investigation; AS: investigation; K-LV: investigation; KT: investigation; MR: investigation; JB: investigation; PE: investigation; HV: investigation; ML-R: investigation, writing—review and editing; VR: investigation; HK: data curation, software, formal analysis, visualization; TSJ: conceptualization, methodology, resources, writing—review and editing; KKE: conceptualization, methodology, project administration, supervision, funding acquisition, investigation, writing—review and editing. All co-authors take full responsibility for all aspects of the work.

Funding

Open access funding provided by University of Helsinki including Helsinki University Central Hospital. This study was supported by an independent research grant from Pfizer (Grant Number WI189027). Pfizer did not have any influence on planning, executing, interpretation or reporting of the data.

Data availability

All data of the study is available upon reasonable request.

Code availability

Not applicable.

Declarations

Footnotes

Contributor Information

J. Hiltunen, Email: [email protected].

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for the FinADASpA Study Group:

References