Association of HLA-DRB1 alleles with clinical responses to the anti-interleukin-17A monoclonal antibody secukinumab in active rheumatoid arthritis.
OBJECTIVE
To assess whether preliminary findings of associations between the HLA-DRB1*04 and HLA-DRB1* shared epitope (SE) allelic groups and response to the anti-IL-17A mAb secukinumab in RA were reproducible in an independent RA cohort.


METHODS
Biologic-naïve subjects (n = 100) with RA by 2010 criteria with tender/swollen joint counts (each ≥6) and high-sensitivity CRP (hsCRP) >10 mg/l were randomized 2:1 to secukinumab 10 mg/kg i.v. or placebo every 2 weeks until week 10. Potential associations with treatment response to secukinumab at week 12 (DAS28-CRP change from baseline by analysis of covariance, ACR20 response rate by logistic regression) were assessed for HLA-DRB1*04 (primary end point), HLA-DRB1*SE and HLA-DRB1 position 11 V/L (HLA-DRB1*pos11 V/L) allelic groups, and baseline levels of hsCRP, RF and anti-CCP.


RESULTS
Secukinumab was significantly more effective than placebo in reducing DAS28-CRP (-2.41 vs -0.71; P < 0.0001) and producing ACR20 responses (87.1% vs 25.0%; P < 0.0001) at week 12. The HLA-DRB1*04 allelic group was not significantly related to secukinumab response vs placebo. For change from baseline in DAS28-CRP, HLA-DRB1*SE (P = 0.003) and HLA-DRB1*pos11 V/L (P = 0.002) allelic groups were associated with positive treatment response. Higher RF levels, but not anti-CCP positivity, were significantly associated with DAS28-CRP reductions (P = 0.015) and ACR20 (P = 0.008) responses. Secukinumab was well tolerated.


CONCLUSIONS
Secukinumab significantly reduced signs and symptoms of RA vs placebo. As the HLA-DRB1*SE and HLA-DRB1*pos11 V/L results were driven by lack of placebo response in carriers, the hypothesis of clinical utility for HLA-DRB1* allelic groups in RA anti-IL-17A short-term response prediction could not be corroborated.


BACKGROUND
ClinicalTrials.gov; https://clinicaltrials.gov/; NCT01426789.
Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Gerd R
GR
Burmester
Service et Pôle de Rhumatologie, Cliniques Universitaires Saint-Luc, and Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Rheumatology, Brussels, Belgium.
Patrick
P
Durez
Department of Internal Medicine, City Clinical Hospital, Nizhny Novgorod, Russia.
Galina
G
Shestakova
Division of Rheumatology and Clinical Immunology, Stanford University, Stanford, CA, USA.
Mark C
MC
Genovese
Division of Rheumatology and Clinical Immunology, Medizinische Klinik and Poliklinik IV, University of Munich, Munich, Germany.
Hendrik
H
Schulze-Koops
Integrated Information Sciences, Novartis Pharma AG, Basel, Switzerland.
Yue
Y
Li
Oncology Global Development/Biometrics and Data Management, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
Ying A
YA
Wang
Translational Medicine/Biomarker Development, Novartis Institutes for Biomedical Research, Cambridge, MA, USA and.
Steve
S
Lewitzky
Translational Medicine/Biomarker Development, Novartis Institutes for Biomedical Research, Cambridge, MA, USA and.
Irina
I
Koroleva
Translational Medicine/Autoimmunity, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Anni Agarwal
AA
Berneis
Translational Medicine/Autoimmunity, Novartis Institutes for Biomedical Research, Basel, Switzerland.
David M
DM
Lee
Translational Medicine/Autoimmunity, Novartis Institutes for Biomedical Research, Basel, Switzerland wolfgang.hueber@novartis.com.
Wolfgang
W
Hueber
D000328:Adult; D000483:Alleles; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D020381:Interleukin-17 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D059811:HLA-DRB1 Chains; C527195:HLA-DRB1*04 antigen; C508717:IL17A protein, human; D020381:Interleukin-17; C555450:secukinumab
C-reactive protein; HLA; biomarker; clinical trial; genetic; interleukin-17; rheumatoid arthritis; rheumatoid factor; secukinumab