Anti-CCP3.1 and Anti-CCP3-IgA Are Elevated in RA-Free Subjects with Idiopathic Pulmonary Fibrosis

Scott Matson¹, Joshua J. Solomon², Jeffrey J. Swigris², Jonathan Chung³, Michael Mahler⁴, Kevin D. Deane⁵ and M. Kristen Demoruelle⁵, ¹Medicine, University of Colorado Denver, Aurora, CO, ²Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, ³Radiology, University of Chicago Medical Center, Chicago, IL, ⁴Research and Development, Inova Diagnostics, San Diego, CA, ⁵Rheumatology Division, University of Colorado Denver, Aurora, CO

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: anti-CCP antibodies, Autoimmunity, interstitial lung disease and rheumatoid arthritis (RA)

Session Information

Date: Sunday, November 13, 2016

Title: Rheumatoid Arthritis – Human Etiology and Pathogenesis - Poster I

Session Type: ACR Poster Session A

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

Background/Purpose: In RA-associated interstitial lung disease (RA-ILD), higher levels of anti-CCP antibodies have been associated with the presence and severity of ILD suggesting a potential role in the pathophysiology. Usual interstitial pneumonia (UIP) is the most common RA-ILD subtype and associated with a poor prognosis. Idiopathic pulmonary fibrosis (IPF) is a distinct form of ILD that is radiographically and pathologically similar to RA-UIP, but the role of anti-CCP in IPF has not been well studied. As such, we sought to compare anti-CCP in subjects with RA-UIP and IPF.

Methods: From the National Jewish Health serum biobank, we identified 36 patients with RA-UIP and 35 patients with IPF without RA (IPF-noRA). Diagnosis was confirmed by chart review. Serum was tested for the commercial assay CCP3.1 (IgG/IgA, Inova) and isotype-specific research assays using the CCP3 substrate for IgG and IgA (Inova). Anti-CCP3.1 positivity was based on manufacturer recommendations, and to evaluate specificity, we also tested 35 healthy Controls who were without RA or ILD based on self-report. For CCP-IgG and IgA assays, cut-off for positivity was set at a level that was positive in <5% in 154 random blood donors. Analyses included comparisons between groups (Chi-square/Fisher’s) and within each group (McNemar’s). Non-parametric testing compared change in diffusing capacity of the lung for carbon monoxide (DLCO) between anti-CCP(+) and (-) subjects.

Results: Subject characteristics are listed in the Table. Overall, anti-CCP3.1 was more prevalent in RA-UIP. However, anti-CCP3.1 positivity was significantly more prevalent in IPF-noRA than Controls (31 vs. 3%, p<0.01). Within IPF-noRA subjects, anti-CCP-IgA was more prevalent than CCP-IgG (31 vs. 6%, p=0.02), but within RA-UIP subjects, anti-CCP-IgA and IgG rates were similar (67 vs. 58%, p=0.45). In addition, 25/35 IPF-noRA and 20/36 RA-UIP subjects had pulmonary function tests at the time of serum collection and longitudinally within 2 years (median 1.1 years, range 0.3-2 years). In IPF-noRA subjects, anti-CCP3.1 and CCP-IgA positive subjects had a poorer prognosis [median decline in DLCO/year; for anti-CCP3.1 (+) vs. (-), 3.48 vs. 0.80, p=0.04; for anti-CCP-IgA (+) vs. (-), 2.78 vs. 0.69, p=0.05]. Similar associations were not seen in RA-UIP where the majority of subjects were anti-CCP (+).

Conclusion: We found that almost one third of IPF-noRA subjects are positive for the commercially available anti-CCP3.1, with isotype-specific testing demonstrating predominately anti-CCP-IgA, and positivity being associated with a more rapid progression of lung disease. Further study is needed to determine whether anti-CCP-IgA in these subjects represents a non-specific response to lung injury or a marker of a novel subset of IPF subjects that may be more responsive to immunosuppressive therapy. Longitudinal follow-up is needed to determine the risk of progression to classifiable RA in IPF-noRA subjects.

Table. Clinical Characteristics and Anti-CCP Positivity in RA-UIP and IPF
	RA-UIP (N=36)	IPF (N=35)	p-value*	IPF (N=35)	Controls (N=35)	p-value**
Age, mean ± SD	64 ± 11	69 ± 8	0.02	69 ± 8	57 ± 7	<0.01
Female, %	50	23	0.02	23	63	<0.01
History of ever smoking, %	54	66	0.33	66	26	<0.01
≥10 pack years of smoking, %	38	50	0.31	50	14	<0.01
Anti-CCP3.1 positivity, %	69	31	<0.01	31	3	<0.01
Anti-CCP3-IgG positivity, %	67***	6***	<0.01	6	–
Anti-CCP3-IgA positivity, %	58***	31***	<0.01	31	–
P-value compares RA-UIP and IPF subjects using t-test for age and Chi-square/Fisher’s exact testing for other variables * P-value compares IPF and healthy Control subjects using t-test for age and Chi-square/Fisher’s exact testing for other variables ***Within IPF subjects using McNemar’s test, anti-CCP3-IgA was significantly more prevalent than CCP3-IgG (31 vs. 6%, p=0.02). However within RA-UIP subjects, anti-CCP3-IgG and CCP3-IgA positivity were not significantly different (67 vs. 58%, p=0.45). Abbreviations: CCP=cyclic citrullinated peptide; RA-UIP = rheumatoid arthritis-associated usual interstitial pneumonia; IPF=idiopathic pulmonary fibrosis

Disclosure: S. Matson, None; J. J. Solomon, None; J. J. Swigris, None; J. Chung, None; M. Mahler, Inova Diagnostics, 3; K. D. Deane, Inova Diagnostics, Inc., 9; M. K. Demoruelle, Inova Diagnostics, Inc., 9.

To cite this abstract in AMA style:

Matson S, Solomon JJ, Swigris JJ, Chung J, Mahler M, Deane KD, Demoruelle MK. Anti-CCP3.1 and Anti-CCP3-IgA Are Elevated in RA-Free Subjects with Idiopathic Pulmonary Fibrosis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/anti-ccp3-1-and-anti-ccp3-iga-are-elevated-in-ra-free-subjects-with-idiopathic-pulmonary-fibrosis/. Accessed .

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