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Advanced targeted therapies including tumour necrosis factor inhibitors (TNFis) have transformed the clinical management of rheumatoid arthritis (RA). However, monoclonal antibody (MAb)-derived TNFis are associated with development of immunogenicity resulting in low circulating drug levels (online supplemental figure S5).1 A genetic predictor of immunogenicity would have clinical utility by providing a pretreatment biomarker that could be used to inform therapy selection. Previous genetic studies of TNFi immunogenicity have focused on alleles within the HLA locus on chromosome 6.2–4
Supplemental material
Patients were followed for 12 months with serum samples collected at 3 months, 6 months and 12 months following commencement on adalimumab (TNFi) therapy. Neutralising antidrug antibodies (ADAs) were detected using a drug-sensitive/drug-tolerant radioimmunoassay (Sanquin, NL). The presence of ADAs was determined by radioimmunoassay. A positive ADA titre was defined as >12 arbitrary units/mL. If a patient developed ADA at any time in the study, they were classed as ADA positive. Genotyping was carried out using the Illumina array, and HLA alleles were imputed using SNP2HLA and the T1DGC reference panel following standard data quality control (full details in online supplemental S1). Drug immunogenicity rates were determined using Kaplan-Meier analysis, and Cox proportional hazards regression, which was used to adjust genetic models for biological sex, age, concurrent conventional synthetic disease-modifying antirheumatic drug (csDMARD) use, disease duration and first within-sample principal component from the genetic dataset.
In total 445 patients were studied, of whom 96 (21.6%) became ADA positive during treatment. A total of 377 (85.3%) patients received cotherapy with csDMARDs of which 302 (81.4%) patients received methotrexate (MTX, online supplemental table S1). Disease duration modestly increased the rate of immunogenicity for every year since RA diagnosis (HR=1.02, p=0.01, table 1). Compared with TNFi monotherapy, combination therapy with csDMARD reduced the rate of ADA development by more than twofold (HR=0.379, p=1.27e−07). Importantly, a statistically significant difference in the rate of immunogenicity was observed when MTX cotherapy was compared with cotherapy with alternative csDMARDs; MTX conferring higher protection from immunogenicity (HR=0.425, p=1.27e−05). However, non-MTX csDMARD use also trended towards a reduced rate of immunogenicity (HR=0.66; 95% CI 0.429 to 1.012, p=0.056).
Cox regression output for the clinical attributes, where N is the number of samples available within each variable
Following quality control of the genetic data, 166 HLA alleles were available for analysis in 435 patients with non-missing covariate data. The most statistically significant association with immunogenicity was observed for HLA-DQA1*03 (HR 0.6; 95% CI 0.474 to 0.775, p=6.4e−05) and HLA-DRB1*04 (HR 0.6; 95% CI 0.476 to 0.775, p=6.3e−05) (4-digit and amino-acid results are reported in online supplemental material S1). In the Kaplan-Meier analysis, carriage of HLA-DQA1*03 and HLA-DRB1*04 alleles under an additive model was associated with reduced rate of immunogenicity (figure 1A–C). The two HLA alleles were in LD (R2: 0.94),5 suggesting a single protective effect. In carriers of at least one copy of HLA-DQA1*03 or HLA-DRB1*04, MTX was observed to provide stronger protection against ADA development compared with other csDMARDs (HR 0.44; 95% CI 0.24 to 0.78, p=5.7e−03, figure 1B–D). We also investigated HLA alleles that have previously been reported on in RA and Crohn’s disease and provide support for alleles at HLA-DQA1*05, HLA-DRB1*11 and HLA-DRB1*03 (online supplemental figure S4).
(A, C) Kaplan-Meier (KM) plot showing rate of drug antidrug antibody development, stratified by the number of HLA alleles carried (A, HLA-DQA1*03; C, HLA-DRB1*04). The tables presented underneath the KM plots represents the number of participants at risk over time. Blue, orange and green indicate 0, 1 and 2 copies of the alleles respectively. (B, D) Kaplan-Meier plot of drug immunogenicity rate for carriers of at least one copy of HLA-DQA1*03 and HLA-DRB1*04, respectively, for different types of csDMARD cotherapy. Solid line and darkest shade of colour represent cotherapy with MTX, dashed line and middle shade represents non-MTX csDMARD, dotted line with the lightest shade represents monotherapy with only adalimumab. csDMARD, conventional synthetic disease modifying antirheumatic drug; MTX, methotrexate.
In conclusion, in the largest study of its type in RA to date, carriage of HLA-DQA1*03 and HLA-DRB1*04 reduced the rate of drug immunogenicity to adalimumab. The strongest protection from immunogenicity was conferred by csDMARD cotherapy, particularly in combination with MTX. Our results suggest that the use of alternative csDMARDs should be encouraged for patients treated with MAb TNFi who are MTX intolerant. Larger studies are now needed to determine if genetic testing could optimise selection of treatment and to quantify effects of non-MTX csDMARDs on immunogenicity.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and ethics was approved by the North West 6 Central Manchester South Research Ethics Committee (COREC 04/Q1403/37) and all patients provided written consent. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We thank Asma Kalei for carefully coordinating sample analysis at Sanquin Diagnostic Services.
Supplementary materials
Supplementary Data
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Footnotes
Handling editor Josef S Smolen
Twitter @chuanfuyap, @ProfJohnIsaacs
Contributors DP and CFY conceived or designed the study and data analyses. NN, AdV and FCL acquired the data. CFY analysed the data. CFY, NN, AB and DP had access to the data. All authors were involved in interpretation of data and reviewed and approved the manuscript’s content before submission. CFY accepts final responsibility for this work and controlled the decision to publish.
Funding This research was supported by the NIHR Manchester Biomedical Research Centre. We thank Versus Arthritis (grant number 21173, grant number 21754 and grant number 21755) for support. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No. 831434 (3TR). The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
Disclaimer The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Competing interests AWM is supported National Institute for Health and Care Research (NIHR) and Medical Research Council (MRC). AWM has acted as consultant for Roche/Chugai, Vifor and AstraZeneca. AWM is member of speakers’ bureaus for Roche/Chugai. AWM is on Data Safety Monitoring Board for GSK and Regeneron/Sanofi. AWM is on the board for MRC and Vasculitis UK. KH has received grant/research support from Pfizer, Bristol Myers Squibb (BMS). KH has received honoraria for speaking at educational meeting by Abbvie. AB is supported by the NIHR Manchester Biomedical Research Centre. AB has received grant/research support from Pfizer, BMS, Scipher Medicine and Galapagos (paid to host institution). AB is member of speakers’ bureaus for Galapagos (paid to host institution). DP has received grant/research support from BMS, Versus Arthritis and European Commission.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
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