Associations of Serum Anti-Malondialdehyde-Acetaldehyde (MAA) Antibodies with Cardiovascular and Respiratory Mortality in Men with Rheumatoid Arthritis

Bryant R. England¹, Geoffrey M. Thiele², Michael J. Duryee³, Lynell Klassen⁴, Jeremy Sokolove⁵, William H. Robinson⁶, Daniel Anderson⁷, Harlan Sayles⁷, Kaleb Michaud⁸, Liron Caplan⁹, Lisa A. Davis⁹, Grant W. Cannon¹⁰, Brian Sauer¹¹, E. Blair Solow¹², Andreas Reimold¹³, Gail S. Kerr¹⁴, Pascale Schwab¹⁵, Joshua F. Baker¹⁶ and Ted R. Mikuls¹⁷, ¹Division of Rheumatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, ²Research Services 151, Omaha VA Medical Center, Omaha, NE, ³Internal Medicine Division of Rheumatology, University of Nebraska Medical Center, Omaha, NE, ⁴Dept of Internal Medicine, Univ of Nebraska Med Ctr, Omaha, NE, ⁵Division of Immunology and Rheumatology, Stanford University Medical Center, Mountain View, CA, ⁶Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, ⁷University of Nebraska Medical Center, Omaha, NE, ⁸Rheumatology & Immunology, University of Nebraska Medical Center and National Data Base for Rheumatic Diseases, Omaha, NE, ⁹Div of Rheumatology, Univ of CO Denver School of Med, Aurora, CO, ¹⁰Division of Rheumatology, Salt Lake City VA Medical Center and University of Utah, Salt Lake City, UT, ¹¹Salt Lake City VA Medical Center and University of Utah, Salt Lake City, UT, ¹²Rheumatology, UT Southwestern Medical Center, Dallas, TX, ¹³Rheumatology, VAMC, University of Texas Southwestern Medical Center, Dallas, TX, ¹⁴VAMC, Georgetown University, Washington, DC, ¹⁵Div Arth & Rheum Dis, Oregon Health & Sci Univ OP09, Portland, OR, ¹⁶Rheumatology, University of Pennsylvania, Philadelphia, PA, ¹⁷Medicine, University of Nebraska Medical Center, Omaha, NE

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: Biomarkers, Cardiovascular disease, death and rheumatoid arthritis (RA), Lung Disease

Session Information

Date: Monday, November 9, 2015

Title: Rheumatoid Arthritis - Clinical Aspects Poster II

Session Type: ACR Poster Session B

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

Background/Purpose: Mortality from cardiovascular (CV) and respiratory causes is increased in rheumatoid arthritis (RA). Predictive serologic biomarkers of these events are lacking. Previously, we have shown anti-malondialdehyde-acetaldehyde (MAA) antibodies to be associated with disease severity in RA. Anti-MAA antibodies also predict coronary artery disease in the general population and are a marker of smoking and alcohol exposure in the lung. The potential of anti-MAA antibodies as biomarkers of CV and respiratory mortality in RA was assessed in conjunction with serum cytokines / chemokines (CK) and anti-citrullinated protein antibodies (ACPA).

Methods: Male participants in the Veterans Affairs RA registry were followed from enrollment until death or December 2013. Using banked serum from enrollment, anti-MAA antibodies were measured with ELISA, CKs were measured using a bead-based multiplex assay, and ACPAs were measured using multiplex antigen array. CK and ACPA scores were calculated from individual CKs and ACPAs. Vital status and cause of death were determined through the National Death Index. Associations with cause-specific mortality were examined using multivariable competing-risks regression adjusting for age, race, smoking status, body mass index, comorbidity, visit frequency, nodules, RF concentration, enrollment DAS-28, baseline DMARDs and prednisone use. Biomarkers were analyzed as log transformed continuous variables and ordinal categorical variables by quartile.

Results: There were 1,552 patients included with 321 all-cause, 100 CV, and 50 respiratory deaths occurring over 5,940 patient-years of follow-up. Patients were older (mean 65 ± 10 years), had established disease (median 8.6 years), were seropositive for RF (81%) or anti-CCP antibody (79%), and had frequent smoking history (83% current or former). Associations with cause-specific mortality are shown in Table 1. IgA and IgM anti-MAA antibodies were associated with respiratory mortality. There was a trend towards an association between both respiratory and CV mortality with increasing IgA anti-MAA antibody quartiles. An inverse association of ACPA score with respiratory mortality was observed, though this did not reach statistical significance.

Table 1. Associations of Serum Anti-MAA Antibodies, Cytokines, and ACPAs with CV and Respiratory Mortality in RA.

All-Cause

Cardiovascular

Respiratory

Hazard Ratio (95% Confidence Interval)

P trend Across Quartiles

IgA anti-MAA

1.13 (1.02-1.24) P = 0.019

P trend < 0.001

1.01 (0.78-1.32) P = 0.92

P trend = 0.062

1.20 (1.02-1.42) P = 0.029

P trend = 0.055

IgM anti-MAA

1.05 (0.95-1.15) P = 0.36

P trend = 0.31

1.00 (0.85-1.19) P = 0.97

P trend = 0.46

1.18 (1.00-1.38) P = 0.05

P trend = 0.43

IgG anti-MAA

0.98 (0.95-1.02) P = 0.33

P trend = 0.51

0.95 (0.71-1.25) P = 0.70

P trend = 0.61

0.93 (0.76-1.15) P = 0.52

P trend = 0.50

Cytokine score

1.21 (1.08-1.36) P = 0.001

P trend = 0.012

1.05 (0.91-1.21)

P = 0.49

P trend = 0.96

1.00 (0.67-1.48) P = 0.99

P trend = 0.51

ACPA score

0.98 (0.90-1.06) P = 0.59

P trend = 0.57

0.97 (0.89-1.05) P = 0.38

P trend = 0.48

0.87 (0.75-1.01) P = 0.06

P trend = 0.14

Abbreviations: MAA, malondialdehyde-acetaldehyde; ACPA, anti-citrullinated protein antibody.

Conclusion: Serum IgA and IgM anti-MAA antibodies predict respiratory mortality in RA independent of disease activity and smoking status, showing promise as a potential biomarker. Further studies are needed to identify the MAA modified peptides driving these antibody responses and to investigate if the observed association is more closely related to smoking-related lung disease (i.e. COPD) or RA-related lung disease (i.e. ILD).

Disclosure: B. R. England, None; G. M. Thiele, None; M. J. Duryee, None; L. Klassen, None; J. Sokolove, None; W. H. Robinson, None; D. Anderson, None; H. Sayles, None; K. Michaud, None; L. Caplan, None; L. A. Davis, None; G. W. Cannon, Amgen, 2; B. Sauer, None; E. B. Solow, None; A. Reimold, None; G. S. Kerr, None; P. Schwab, None; J. F. Baker, None; T. R. Mikuls, None.

To cite this abstract in AMA style:

England BR, Thiele GM, Duryee MJ, Klassen L, Sokolove J, Robinson WH, Anderson D, Sayles H, Michaud K, Caplan L, Davis LA, Cannon GW, Sauer B, Solow EB, Reimold A, Kerr GS, Schwab P, Baker JF, Mikuls TR. Associations of Serum Anti-Malondialdehyde-Acetaldehyde (MAA) Antibodies with Cardiovascular and Respiratory Mortality in Men with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/associations-of-serum-anti-malondialdehyde-acetaldehyde-maa-antibodies-with-cardiovascular-and-respiratory-mortality-in-men-with-rheumatoid-arthritis/. Accessed .

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