title: HLA alleles as biomarkers of high-titre neutralising antibodies to interferon-β therapy in multiple sclerosis.
abstract: BACKGROUND
  Recombinant interferon β (IFNβ) is a first-line therapy for relapsing-remitting multiple sclerosis (MS), with a proven effect on the inflammatory activity. Neutralising antibodies against IFNβ (NAbs) promote a loss of IFNβ bioactivity in a titre-dependent way and their development was associated with certain human leucocyte antigen (HLA) alleles. We investigated the contribution conferred by HLA alleles on the development of NAbs in independent cohorts of Southern Europe.
  
  
  METHODS
  Serum NAbs from 610 MS patients with HLA-genotype data were evaluated by cytopathic effect assay: negative tests included at least one negative result (NAb titres<20 NU/mL) after 1 year treatment; NAb-titres ≥20 NU/mL were positive tests and NAb titres ≥150 NU/mL in any test were classified as high-titre positives.
  
  
  RESULTS
  The combined presence of DRB1*07/DQA1*02 with A*26 or B*14 was found in 20% of patients with NAbs at high titres, but only in 5.4% of NAb-negative patients (p=0.00052, OR (95% CI) 4.34 (1.85 to 10.13)). The DRB1*04:01 allele was also more frequently carried by patients with high titres of NAbs (10% vs 4.5%; p=0.046, OR (95% CI) 2.38 (0.93 to 5.92)). The alleles carried at a significantly lower frequency in patients with high persistent NAbs corresponded to the A*11 allele (3.3% vs 13.8%; p=0.023, OR (95% CI) 0.22 (0.02 to 0.87)), as well as the DRB1*03/DQA1*05/DQB1*02 haplotype (16.3% vs 26.8%; p=0.02, OR (95% CI) 0.53 (0.27 to 1.03)) and the DRB1*13/DQA1*01:03/DQB1*06:03 haplotype (2.5% vs 9.1%; p=0.045, OR (95% CI) 0.25 (0.03 to 1.02)).
  
  
  CONCLUSIONS
  50% of the studied MS patients carried some of the five independently associated HLA allele/allele combinations described in this work. This relevant percentage of patients could benefit a therapeutic decision.
authors.affiliation: Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Núñez
authors.affiliation: Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Cénit
authors.affiliation: Multiple Sclerosis Unit, Neurology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Alvarez-Lafuente
authors.affiliation: Department of Neurology-Neuroimmunology, Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Río
authors.affiliation: Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Fernández-Arquero
authors.affiliation: Multiple Sclerosis Unit, Neurology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Arroyo
authors.affiliation: Department of Neurology-Neuroimmunology, Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalbán
authors.affiliation: Servicio de Neurología, Instituto de Neurociencias Clínicas, Hospital Regional Universitario, Málaga, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernández
authors.affiliation: Laboratorio de Investigación, Instituto de Neurociencias Clínicas, Hospital Regional Universitario, Málaga, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Oliver-Martos
authors.affiliation: Laboratorio de Investigación, Instituto de Neurociencias Clínicas, Hospital Regional Universitario, Málaga, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Leyva
authors.affiliation: Department of Neurology-Neuroimmunology, Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.affiliation: Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
mesh_terms: D000328:Adult; D000483:Alleles; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D005260:Female; D059848:HLA-DQ alpha-Chains / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016899:Interferon-beta / Q000276:immunology* / Q000627:therapeutic use*; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D010597:Pharmacogenetics / Q000379:methods
chemical_list: D057134:Antibodies, Neutralizing; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D059811:HLA-DRB1 Chains; C456920:HLA-DRB1*07 antigen; D016899:Interferon-beta