Autoantibodies to peptidylarginine deiminase 2 are associated with less severe disease in rheumatoid arthritis

Erika Darrah, Jon T. Giles, Ryan L. Davis, Pooja Naik, Hong Wang, Maximilian F. Konig, Laura Cappelli, Clifton Bingham, Sonye Danoff, Felipe A Andrade

Research output: Contribution to journalArticle

Abstract

Objective: Peptidylarginine deiminases (PAD) 2 and 4 are key enzymes in rheumatoid arthritis (RA) pathogenesis due to their ability to generate the protein targets of anti-citrullinated protein antibodies (ACPA). Anti-PAD4 antibodies that cross-react with PAD3 (anti-PAD3/4) have been identified and are associated with severe joint and lung disease. Here, we examined whether anti-PAD2 antibodies were present in patients with RA and defined their clinical significance. Patients and Methods: A PAD2 ELISA was established to screen for anti-PAD2 IgG in sera from RA patients from a prospective observational cohort study (n = 184) and healthy controls (n = 100). RA patient characteristics were compared according to anti-PAD2 antibody status. Multivariable models were constructed to explore the independent associations of anti-PAD2 antibodies with clinical variables. Results: Anti-PAD2 antibodies were found in 18.5% of RA patients and 3% of healthy controls (p < 0.001). Among RA patients, anti-PAD2 antibodies were not associated with traditional genetic or serologic RA risk factors, including HLA-DRβ1 shared epitope alleles, ACPA, rheumatoid factor (RF), or anti-PAD3/4 antibodies. In addition, antibodies to PAD2 were associated with fewer swollen joints, a lower prevalence of interstitial lung disease, and less progression of joint damage. In subset analyses in which patients were stratified by the baseline presence of ACPA/RF or anti-PAD3/4 antibodies, anti-PAD2 antibodies provided additional value in identifying patients with the least progressive joint disease. Conclusions: Anti-PAD2 antibodies represent a novel serologic marker in RA that identifies a genetically and clinically unique subset of patients with less severe joint and lung disease.

Original languageEnglish (US)
Article number02696
JournalFrontiers in Immunology
Volume9
Issue numberNOV
DOIs
StatePublished - Nov 20 2018

Fingerprint

Autoantibodies
Rheumatoid Arthritis
Anti-Idiotypic Antibodies
Antibodies
Joint Diseases
Rheumatoid Factor
Lung Diseases
Proteins
HLA-DR1 Antigen
Joints
protein-arginine deiminase
Interstitial Lung Diseases
Observational Studies
Disease Progression
Epitopes
Cohort Studies
Enzyme-Linked Immunosorbent Assay
Alleles
Enzymes
Serum

Keywords

  • Autoantibodies
  • Autoimmunity
  • Disease activity
  • Interstitial lung disease
  • Peptidylarginine deiminase
  • Rheumatoid arthritis
  • Shared epitope
  • Sharp score

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Autoantibodies to peptidylarginine deiminase 2 are associated with less severe disease in rheumatoid arthritis. / Darrah, Erika; Giles, Jon T.; Davis, Ryan L.; Naik, Pooja; Wang, Hong; Konig, Maximilian F.; Cappelli, Laura; Bingham, Clifton; Danoff, Sonye; Andrade, Felipe A.

In: Frontiers in Immunology, Vol. 9, No. NOV, 02696, 20.11.2018.

Research output: Contribution to journalArticle

@article{882ab8d7f3cc41f385c53d765f95c5e8,
title = "Autoantibodies to peptidylarginine deiminase 2 are associated with less severe disease in rheumatoid arthritis",
abstract = "Objective: Peptidylarginine deiminases (PAD) 2 and 4 are key enzymes in rheumatoid arthritis (RA) pathogenesis due to their ability to generate the protein targets of anti-citrullinated protein antibodies (ACPA). Anti-PAD4 antibodies that cross-react with PAD3 (anti-PAD3/4) have been identified and are associated with severe joint and lung disease. Here, we examined whether anti-PAD2 antibodies were present in patients with RA and defined their clinical significance. Patients and Methods: A PAD2 ELISA was established to screen for anti-PAD2 IgG in sera from RA patients from a prospective observational cohort study (n = 184) and healthy controls (n = 100). RA patient characteristics were compared according to anti-PAD2 antibody status. Multivariable models were constructed to explore the independent associations of anti-PAD2 antibodies with clinical variables. Results: Anti-PAD2 antibodies were found in 18.5{\%} of RA patients and 3{\%} of healthy controls (p < 0.001). Among RA patients, anti-PAD2 antibodies were not associated with traditional genetic or serologic RA risk factors, including HLA-DRβ1 shared epitope alleles, ACPA, rheumatoid factor (RF), or anti-PAD3/4 antibodies. In addition, antibodies to PAD2 were associated with fewer swollen joints, a lower prevalence of interstitial lung disease, and less progression of joint damage. In subset analyses in which patients were stratified by the baseline presence of ACPA/RF or anti-PAD3/4 antibodies, anti-PAD2 antibodies provided additional value in identifying patients with the least progressive joint disease. Conclusions: Anti-PAD2 antibodies represent a novel serologic marker in RA that identifies a genetically and clinically unique subset of patients with less severe joint and lung disease.",
keywords = "Autoantibodies, Autoimmunity, Disease activity, Interstitial lung disease, Peptidylarginine deiminase, Rheumatoid arthritis, Shared epitope, Sharp score",
author = "Erika Darrah and Giles, {Jon T.} and Davis, {Ryan L.} and Pooja Naik and Hong Wang and Konig, {Maximilian F.} and Laura Cappelli and Clifton Bingham and Sonye Danoff and Andrade, {Felipe A}",
year = "2018",
month = "11",
day = "20",
doi = "10.3389/fimmu.2018.02696",
language = "English (US)",
volume = "9",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S. A.",
number = "NOV",

}

TY - JOUR

T1 - Autoantibodies to peptidylarginine deiminase 2 are associated with less severe disease in rheumatoid arthritis

AU - Darrah, Erika

AU - Giles, Jon T.

AU - Davis, Ryan L.

AU - Naik, Pooja

AU - Wang, Hong

AU - Konig, Maximilian F.

AU - Cappelli, Laura

AU - Bingham, Clifton

AU - Danoff, Sonye

AU - Andrade, Felipe A

PY - 2018/11/20

Y1 - 2018/11/20

N2 - Objective: Peptidylarginine deiminases (PAD) 2 and 4 are key enzymes in rheumatoid arthritis (RA) pathogenesis due to their ability to generate the protein targets of anti-citrullinated protein antibodies (ACPA). Anti-PAD4 antibodies that cross-react with PAD3 (anti-PAD3/4) have been identified and are associated with severe joint and lung disease. Here, we examined whether anti-PAD2 antibodies were present in patients with RA and defined their clinical significance. Patients and Methods: A PAD2 ELISA was established to screen for anti-PAD2 IgG in sera from RA patients from a prospective observational cohort study (n = 184) and healthy controls (n = 100). RA patient characteristics were compared according to anti-PAD2 antibody status. Multivariable models were constructed to explore the independent associations of anti-PAD2 antibodies with clinical variables. Results: Anti-PAD2 antibodies were found in 18.5% of RA patients and 3% of healthy controls (p < 0.001). Among RA patients, anti-PAD2 antibodies were not associated with traditional genetic or serologic RA risk factors, including HLA-DRβ1 shared epitope alleles, ACPA, rheumatoid factor (RF), or anti-PAD3/4 antibodies. In addition, antibodies to PAD2 were associated with fewer swollen joints, a lower prevalence of interstitial lung disease, and less progression of joint damage. In subset analyses in which patients were stratified by the baseline presence of ACPA/RF or anti-PAD3/4 antibodies, anti-PAD2 antibodies provided additional value in identifying patients with the least progressive joint disease. Conclusions: Anti-PAD2 antibodies represent a novel serologic marker in RA that identifies a genetically and clinically unique subset of patients with less severe joint and lung disease.

AB - Objective: Peptidylarginine deiminases (PAD) 2 and 4 are key enzymes in rheumatoid arthritis (RA) pathogenesis due to their ability to generate the protein targets of anti-citrullinated protein antibodies (ACPA). Anti-PAD4 antibodies that cross-react with PAD3 (anti-PAD3/4) have been identified and are associated with severe joint and lung disease. Here, we examined whether anti-PAD2 antibodies were present in patients with RA and defined their clinical significance. Patients and Methods: A PAD2 ELISA was established to screen for anti-PAD2 IgG in sera from RA patients from a prospective observational cohort study (n = 184) and healthy controls (n = 100). RA patient characteristics were compared according to anti-PAD2 antibody status. Multivariable models were constructed to explore the independent associations of anti-PAD2 antibodies with clinical variables. Results: Anti-PAD2 antibodies were found in 18.5% of RA patients and 3% of healthy controls (p < 0.001). Among RA patients, anti-PAD2 antibodies were not associated with traditional genetic or serologic RA risk factors, including HLA-DRβ1 shared epitope alleles, ACPA, rheumatoid factor (RF), or anti-PAD3/4 antibodies. In addition, antibodies to PAD2 were associated with fewer swollen joints, a lower prevalence of interstitial lung disease, and less progression of joint damage. In subset analyses in which patients were stratified by the baseline presence of ACPA/RF or anti-PAD3/4 antibodies, anti-PAD2 antibodies provided additional value in identifying patients with the least progressive joint disease. Conclusions: Anti-PAD2 antibodies represent a novel serologic marker in RA that identifies a genetically and clinically unique subset of patients with less severe joint and lung disease.

KW - Autoantibodies

KW - Autoimmunity

KW - Disease activity

KW - Interstitial lung disease

KW - Peptidylarginine deiminase

KW - Rheumatoid arthritis

KW - Shared epitope

KW - Sharp score

UR - http://www.scopus.com/inward/record.url?scp=85057381310&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057381310&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2018.02696

DO - 10.3389/fimmu.2018.02696

M3 - Article

C2 - 30515171

AN - SCOPUS:85057381310

VL - 9

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - NOV

M1 - 02696

ER -