Anti-Citrullinated Protein Antibody and Radiographic Disease Progression in Rheumatoid Arthritis

Brian Coburn¹, Geoffrey M. Thiele¹, Michael J. Duryee², Fang Yu³, Harlan Sayles⁴, Jeremy Sokolove⁵, WH Robinson⁶, Alan Erickson⁷, Mary Brophy⁸, James R. O'Dell¹ and Ted R. Mikuls¹, ¹Omaha VA Medical Center and University of Nebraska Medical Center, Omaha, NE, ²Internal Medicine Division of Rheumatology, University of Nebraska Medical Center, Omaha, NE, ³Public Health, University of Nebraska Medical Center, Omaha, NE, ⁴University of Nebraska Medical Center, Omaha, NE, ⁵Stanford University, Palo Alto, CA, ⁶VA Palo Alto Health Care System and Stanford University, Palo Alto, CA, ⁷University of Nebraska College of Medicine and VA Nebraska Western Iowa Health Care System, Omaha, NE, ⁸VA Boston Heathcare System, Boston, MA

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: ACPA, outcomes and rheumatoid arthritis (RA)

Session Information

Date: Tuesday, November 10, 2015

Title: Rheumatoid Arthritis - Clinical Aspects Poster Session III

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:

Anti-citrullinated protein antibody (ACPA) positivity is
associated with more rapid radiographic progression in rheumatoid arthritis
(RA). A majority of prior studies, however, have assessed ACPA status using
only the commercially available anti-CCP2 antibody assay. Thus, it is unknown
to what extent any antigen-specific ACPA might drive this relationship. The
objective of this study was to simultaneously evaluate the association between
anti-CCP2 antibody and antigen-specific ACPA with radiographic disease
progression in a well-characterized cohort.

Methods:

This is a
secondary analysis of the 48-week Rheumatoid Arthritis Comparison of Active
Therapies (RACAT) trial. RA patients with active disease despite
methotrexate (MTX) were randomized to receive triple therapy (MTX +
sulfasalazine/hydroxychloroquine) or MTX + etanercept. Baseline serum was tested for anti-CCP2 using a
commercially available ELISA and 29 antigen-specific ACPA using a multiplex
peptide array (Table footnote). Radiographs from baseline, 24- and 48-weeks
were scored by blinded experts using a modified Sharp score. Generalized linear
mixed effects models assuming a negative binomial distribution were used to model
associations of ACPA with Sharp scores over time. Models were adjusted for age,
gender, race, smoking status, BMI and disease duration. Statistical
significance was defined at a p-value < 0.05 after adjusting for multiple
comparisons using the Benjamini-Hochberg method.

Results:

RA patients
(n=281) had a mean (± SD) age of 56 (12) years, 88% were white and 58% were
male. Although not reaching statistical significance, anti-CCP2 positive
patients had higher baseline Sharp scores compared with anti-CCP2 negative
patients (16.1 vs. 11.1; p=0.45). In adjusted analyses modeling for Sharp
scores, anti-CCP2 positivity was associated with 1.14 to 1.18 times the
radiographic progression of anti-CCP2 negative patients at 24 and 48 weeks
(p=0.01) (Table). Assessing ACPA fine specificity, only antibody to citrullinated histone 2A concentration was associated
radiographic progression; each natural log unit increase was associated with
1.05 and 1.06 times higher Sharp score changes from baseline to 24 and 48
weeks, respectively (p=0.0007). No other antigen-specific ACPA were
significantly associated with radiographic scores after adjusting for multiple
comparisons.

Conclusion:

These novel
findings suggest that the well-described association of ACPA positivity with
structural joint damage in RA, may at least in part of driven by autoantibody
targeting citrullinated histone 2A. In addition to
required verification in an independent cohort, future efforts will be needed
to identify the “source” of this autoantigen and
mechanisms underpinning the relationship of this antigen-specific ACPA with
radiographic disease progression.

Table 1 Associations of ACPA with change in modified Sharp scores over time.
Variable	Visit	Exponential of Coefficient^‡	P
Anti-CCP2 Positive	24 Weeks	1.14	0.01
	48 Weeks	1.18
Histone 2A [1-20] cit cyclic^†	24 Weeks	1.05	0.0007*
	48 Weeks	1.06
Histone 2B [62-81] cit cyclic^†	24 Weeks	1.05	0.006**
	48 Weeks	1.05
Histone 2A [1-20] cit sm2 cyclic^†	24 Weeks	1.04	0.007**
	48 Weeks	1.05
^‡ Represents an interaction with visit date indicating a significant difference in Sharp score changes over time by anti-CCP2 status or log-transformed ACPA level. ^† Numbers in brackets indicate the amino acid sequence of the peptide. The Histone 2A peptides are homologous with differing cyclization chemistry. * p < 0.05 after Benjamini-Hochberg adjustment; ** p ≥ 0.05 after Benjamini-Hochberg adjustment. Citrullinated peptides / proteins examined: Fibrinogen (n=10); Apolipoprotein A1 (n=2); Apolipoprotein E (n=2); Enolase 1A (n=1); Vimentiin (n=3); Histone 2A (n=3); Histone 2B (n=2); Filaggrin (n=1); Clusterin (n=2); Biglycan (n=1) and Fibronectin (n=2).

Disclosure: B. Coburn, None; G. M. Thiele, None; M. J. Duryee, None; F. Yu, None; H. Sayles, None; J. Sokolove, Bristol-Myers Squibb, 2; W. Robinson, None; A. Erickson, None; M. Brophy, None; J. R. O'Dell, None; T. R. Mikuls, None.

To cite this abstract in AMA style:

Coburn B, Thiele GM, Duryee MJ, Yu F, Sayles H, Sokolove J, Robinson W, Erickson A, Brophy M, O'Dell JR, Mikuls TR. Anti-Citrullinated Protein Antibody and Radiographic Disease Progression in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/anti-citrullinated-protein-antibody-and-radiographic-disease-progression-in-rheumatoid-arthritis/. Accessed .

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