title: Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B cells in rheumatoid arthritis after vaccination with a conjugate pneumococcal vaccine.
abstract: Treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) leads to decreased total immunoglobulin (Ig) levels and impairs vaccine-specific IgG antibody levels following pneumococcal vaccination. The mechanisms by which MTX exerts these effects in RA are unknown. We aimed to evaluate whether MTX reduces vaccine-specific serum Ig levels and their functionality in RA patients following vaccination with pneumococcal conjugate vaccine, and if numbers of antigen-specific circulating plasmablasts are affected.
  
  
  
  Ten patients with RA on MTX and 10 RA patients without disease modifying anti-rheumatic drug (DMARD) were immunized with a dose 13-valent pneumococcal conjugate vaccine (Prevenar13). Circulating plasmablasts producing total IgG and IgA as well as specific IgG and IgA against two pneumococcal capsular serotypes (6B and 23F) were enumerated using ELISPOT 6days after vaccination. IgG levels against both these serotypes were determined with ELISA before and 4-6weeks after vaccination. Positive antibody response was defined as ⩾2-fold increase of pre-vaccination antibody levels. The functionality of vaccine specific antibodies to serotype 23F was evaluated by measuring their ability to opsonize bacteria using opsonophagocytic assay (OPA) in 4 randomly chosen RA patients on MTX and 4 RA patients without DMARD.
  
  
  
  After vaccination, RA patients on MTX showed significant increase in pre- to postvaccination antibody levels for 6B (p<0.05), while patients without DMARD had significant increases for both 6B and 23F (p<0.05 and p<0.01, respectively). Only 10% of RA on MTX and 40% of RA patients without DMARD showed positive post-vaccination antibody responses for both serotypes. Increased opsonizing ability after vaccination was detected in 1 of 4 RA patients on MTX and 3 of 4 patients on RA without DMARD. However, numbers of circulating total and vaccine-specific IgG- or IgA-producing plasmablasts did not differ between RA patients with or without MTX.
  
  
  
  MTX treatment in RA leads to reduced vaccine-specific antibody responses and their functionality compared to untreated RA following pneumococcal vaccination using polysaccharide-protein conjugate vaccine. However, since there was no reduction in numbers of circulating total or vaccine-specific antibody-producing plasmablasts after vaccination this effect is probably not due to reduced activation of B cells in lymphoid tissue.
  
  
  
  NCT02240888.
authors.affiliation: Department of Clinical Sciences, Skåne University Hospital, Lund, Section for Rheumatology, Sweden. Electronic address: meliha.c_kapetanovic@med.lu.se.
authors.forename: Meliha C
authors.initials: MC
authors.lastname: Kapetanovic
authors.affiliation: Department of Clinical Sciences, Skåne University Hospital, Lund, Section for Rheumatology, Sweden. Electronic address: johanna.nagel@gmail.com.
authors.forename: Johanna
authors.initials: J
authors.lastname: Nagel
authors.affiliation: Department of Rheumatology & Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: inger.nordstrom@microbio.gu.se.
authors.forename: Inger
authors.initials: I
authors.lastname: Nordström
authors.affiliation: Department of Clinical Sciences, Skåne University Hospital, Lund, Section for Rheumatology, Sweden. Electronic address: tore.saxne@med.lu.se.
authors.forename: Tore
authors.initials: T
authors.lastname: Saxne
authors.affiliation: Department of Clinical Sciences, Skåne University Hospital, Lund, Section for Rheumatology, Sweden. Electronic address: pierre.geborel@med.lu.se.
authors.forename: Pierre
authors.initials: P
authors.lastname: Geborek
authors.affiliation: Department of Rheumatology & Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Electronic address: anna.rudin@microbio.gu.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Rudin
mesh_terms: D000328:Adult; D000368:Aged; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D018655:Lymphocyte Count; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D022242:Pneumococcal Vaccines / Q000008:administration & dosage*; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D065288:Serogroup; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000254:growth & development / Q000276:immunology; D018074:Vaccines, Conjugate
chemical_list: C538862:13-valent pneumococcal vaccine; D000907:Antibodies, Bacterial; D018501:Antirheumatic Agents; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D022242:Pneumococcal Vaccines; D018074:Vaccines, Conjugate; D008727:Methotrexate
keywords: Antibody responses; Circulating B cells; Methotrexate; Pneumococcal vaccination; Rheumatoid arthritis