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POS0007 (2022)
HLA-DQ2 IS ASSOCIATED WITH ANTI-DRUG ANTIBODY FORMATION TO INFLIXIMAB ACROSS IMMUNE-MEDIATED INFLAMMATORY DISEASES
M. K. Brun1,2, K. H. Bjørlykke3, M. K. Viken4,5, B. Stenvik1, R. A. Klaasen6, J. Gehin6, D. J. Warren6, J. Sexton1, Ø. Sandanger7, C. Mørk8, T. K. Kvien1,9, E. A. Haavardsholm1,2, J. Jahnsen2,3, G. L. Goll1, B. A. Lie2,4,5, K. K. Jørgensen3, N. Bolstad6, S. W. Syversen1
1Diakonhjemmet Hospital, Division of Rheumatology and Research, Oslo, Norway
2University of Oslo, Institute of Clinical Medicine, Oslo, Norway
3Akershus University Hospital, Gastroenterology, Lørenskog, Norway
4Oslo University Hospital, Medical Genetics, Oslo, Norway
5Oslo University Hospital, Immunology, Oslo, Norway
6Oslo University Hospital, Department of Medical Biochemistry, Oslo, Norway
7Oslo University Hospital, Dermatology, Oslo, Norway
8Akershus Dermatology Center, Akershus Dermatology Center, Lørenskog, Norway
9Oslo University Hospital, Institute of Clinical Medicine, Oslo, Norway

Background: Immunogenicity is a leading cause of treatment failure to TNF inhibitors, and also affects drug safety. Variations in HLA class II genes have been suggested to predispose to anti-drug antibody formation (ADA), but characterisation of biologically relevant HLA haplotypes, based on high-resolution genotyping, is lacking.


Objectives: To assess associations between HLA loci and formation of ADA to infliximab across different immune mediated inflammatory diseases.


Methods: Patients with immune mediated inflammatory diseases on infliximab therapy (N=612; 181 spondyloarthritis, 120 rheumatoid arthritis, 72 psoriatic arthritis, 114 ulcerative colitis, 80 Crohn’s disease and 45 psoriasis) participating in the Norwegian Drug Monitoring (NOR-DRUM) trials (1, 2) were included in the present analyses. Neutralising ADA were assessed with an automated fluorescence assay at each infusion. Next generation sequencing-based HLA typing was performed. Associations with ADA formation were assessed at locus, allele, haplotype and amino acid level. Peptide binding predictions for infliximab were performed.


Results: ADA were detected in 147 patients (24%). Significant associations were shown between ADA and several HLA loci, whereas conditional analyses indicated HLA-DQB1 (p=1.4x10-6) as the primary risk locus. Highest risk of ADA formation was seen for patients carrying at least one of the HLA-DQ2 haplotypes; DQB1*02:01~DQA1*05:01 and DQB1*02:02~DQA1*02:01 (OR 3.18, 95% CI 2.15 to 4.69, p=5.9x10-9) ( Figure 1 ). These findings were consistent across diagnoses ( Table 1 ), and remained significant when adjusting for other possible predictors of ADA. Computational predictions indicated that both these HLA-DQ2 haplotypes could strongly bind two peptide motifs (INTVESEDI and VYACEVTHQ) in the infliximab heavy and light chain.

HLA-DQ2 carrier frequencies according to the different disease phenotypes and for all diagnosis combined

Diagnosis HLA-DQ2 carrier-frequency among patients with ADA formation HLA-DQ2 carrier-frequency among patients without ADA formation P-value
RA (N=120) 0.316 0.134 0.02
PsA (N=72) 0.55 0.231 0.01
SpA (N=181) 0.364 0.182 0.02
UC (N=114) 0.556 0.264 0.006
CD (N=80) 0.429 0.303 0.33
Ps (N=45) 0.867 0.267 0.0004
All disease phenotypes 0.469 0.217 5.9x10 -9

Conclusion: The risk of ADA to infliximab was three-fold higher in patients carrying the HLA-DQ2 risk haplotypes across diseases. A biological role for the HLA-DQ2 molecules encoded by the two different HLA-DQ2 risk haplotypes in the formation of ADA was further supported by peptide binding predictions. These novel findings provide promise for future incorporation of HLA-DQ2 testing to facilitate personalised treatment decisions.


REFERENCES:

[1]Syversen SW et al. Jama. 2021;326(23):2375-84.

[2]Syversen SW et al. Jama. 2021;325(17):1744-54.


Disclosure of Interests: Marthe Kirkesæther Brun: None declared, Kristin Hammersbøen Bjørlykke: None declared, Marte K. Viken: None declared, Bitte Stenvik Employee of: is a former employee of UCB Pharma, Rolf A. Klaasen: None declared, Johanna Gehin: None declared, David J Warren: None declared, Joe Sexton: None declared, Øystein Sandanger: None declared, Cato Mørk Speakers bureau: Novartis Norway, LEO Pharma, ACO Hud Norge, Cellgene, Abbvie, and Galderma Nordic AB., Consultant of: Novartis Norway, LEO Pharma, ACO Hud Norge, Cellgene, Abbvie, and Galderma Nordic AB., Tore K. Kvien Speakers bureau: Amgen, Celltrion, Evapharma, Gilead, Hikma, Mylan, Oktal, Pfizer, Sandoz, Sanofi, UCB, Consultant of: Amgen, Celltrion, Evapharma, Gilead, Hikma, Mylan, Oktal, Pfizer, Sandoz, Sanofi, UCB, Grant/research support from: AbbVie, Amgen, BMS, Novartis, Pfizer, UCB, Espen A Haavardsholm Speakers bureau: Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli-Lilly, and UCB, Consultant of: Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli-Lilly, and UCB, Jørgen Jahnsen Speakers bureau: AbbVie, Boerhinger Ingelheim, BMS, Celltrion, Giliad, Hikma, Janssen Cilag, Novartis, Orion Pharma, Pfizer, Roche, Takeda, and Sandoz, Consultant of: AbbVie, Boerhinger Ingelheim, BMS, Celltrion, Giliad, Hikma, Janssen Cilag, Novartis, Orion Pharma, Pfizer, Roche, Takeda, and Sandoz, Guro Løvik Goll Speakers bureau: Pfizer, AbbVie, Boehringer Ingelheim, Roche, Orion pharma, Sandoz, Novartis, and UCB, Consultant of: Pfizer, AbbVie, Boehringer Ingelheim, Roche, Orion pharma, Sandoz, Novartis, and UCB, Benedicte A. Lie: None declared, Kristin Kaasen Jørgensen Speakers bureau: Roche, BMS, Celltrion, and Norgine., Consultant of: Roche, BMS, Celltrion, and Norgine., Nils Bolstad Speakers bureau: Roche Pharmaceuticals and Novartis, Consultant of: Janssen, Silje Watterdal Syversen: None declared

Citation: , volume 81, supplement 1, year 2022, page 216
Session: Challenges in measuring and predicting RMDs (Poster Tours)