Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2016

Open Access 01-12-2016 | Research article

Differential response of serum amyloid A to different therapies in early rheumatoid arthritis and its potential value as a disease activity biomarker

Authors: Yong Gil Hwang, Goundappa K. Balasubramani, Ilinca D. Metes, Marc C. Levesque, S. Louis Bridges Jr., Larry W. Moreland

Published in: Arthritis Research & Therapy | Issue 1/2016

Login to get access

Abstract

Background

The aim was to compare the effect of etanercept (ETN) and conventional synthetic disease-modifying anti-rheumatic drug (DMARD) therapy on serum amyloid A (SAA) levels and to determine whether SAA reflects rheumatoid arthritis (RA) disease activity better than C-reactive protein (CRP).

Methods

We measured SAA and CRP at baseline, 24, 48, and 102 week follow-up visits in 594 patients participating in the Treatment of early RA (TEAR) study. We used Spearman correlation coefficients (rho) to evaluate the relationship between SAA and CRP and mixed effects models to determine whether ETN and methotrexate (MTX) treatment compared to triple DMARD therapy differentially lowered SAA. Akaike information criteria (AIC) were used to determine model fits.

Results

SAA levels were only moderately correlated with CRP levels (rho = 0.58, p < 0.0001). There were significant differences in SAA by both visit (p = 0.0197) and treatment arm (p = 0.0130). RA patients treated with ETN plus MTX had a larger reduction in SAA than patients treated with traditional DMARD therapy. Similar results were found for serum CRP by visit (p = 0.0254) and by treatment (p < 0.0001), with a more pronounced difference than for SAA. Across all patients and time points, models of the disease activity score of 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) using SAA levels were better than models using CRP; the ΔAIC between the SAA and CRP models was 305.

Conclusions

SAA may be a better biomarker of RA disease activity than CRP, especially during treatment with tumor necrosis factor (TNF) antagonists. This warrants additional studies in other cohorts of patients on treatment for RA.

Trial registration

(ClinicalTrials.gov identifier: NCT00259610, Date of registration: 28 November 2005)
Literature
1.
Thompson PW, Silman AJ, Kirwan JR, Currey HL. Articular indices of joint inflammation in rheumatoid arthritis. Correlation with the acute-phase response. Arthritis Rheum. 1987;30(6):618–23.CrossRefPubMed
2.
Devlin J, Gough A, Huissoon A, Perkins P, Holder R, Reece R, et al. The acute phase and function in early rheumatoid arthritis. C-reactive protein levels correlate with functional outcome. J Rheumatol. 1997;24(1):9–13.PubMed
3.
van Leeuwen MA, van Rijswijk MH, van der Heijde DM, Te Meerman GJ, van Riel PL, Houtman PM, et al. The acute-phase response in relation to radiographic progression in early rheumatoid arthritis: a prospective study during the first three years of the disease. Br J Rheumatol. 1993;32 Suppl 3:9–13.CrossRefPubMed
4.
van Leeuwen MA, van der Heijde DM, van Rijswijk MH, Houtman PM, van Riel PL, van de Putte LB, et al. Interrelationship of outcome measures and process variables in early rheumatoid arthritis. A comparison of radiologic damage, physical disability, joint counts, and acute phase reactants. J Rheumatol. 1994;21(3):425–9.PubMed
5.
Prevoo ML, MA v ‘t, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44–8.CrossRefPubMed
6.
van Gestel AM, Prevoo ML, Hof MA v ‘t, van Rijswijk MH, van de Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum. 1996;39(1):34–40.CrossRefPubMed
7.
Osei-Bimpong A, Meek JH, Lewis SM. ESR or CRP? A comparison of their clinical utility. Hematology. 2007;12(4):353–7.CrossRefPubMed
8.
Siemons L, Ten Klooster PM, Vonkeman HE, van Riel PL, Glas CA, van de Laar MA. How age and sex affect the erythrocyte sedimentation rate and C-reactive protein in early rheumatoid arthritis. BMC Musculoskelet Disord. 2014;15:368.CrossRefPubMedPubMedCentral
9.
Wells G, Becker JC, Teng J, Dougados M, Schiff M, Smolen J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis. 2009;68(6):954–60.CrossRefPubMedPubMedCentral
10.
Sokka T, Pincus T. Erythrocyte sedimentation rate, C-reactive protein, or rheumatoid factor are normal at presentation in 35 %-45% of patients with rheumatoid arthritis seen between 1980 and 2004: analyses from Finland and the United States. J Rheumatol. 2009;36(7):1387–90.CrossRefPubMed
11.
Pincus T, Gibson KA, Shmerling RH. An evidence-based approach to laboratory tests in usual care of patients with rheumatoid arthritis. Clin Exp Rheumatol. 2014;32(5 Suppl 85):S-23–8.
12.
Wolfe F, Michaud K. The clinical and research significance of the erythrocyte sedimentation rate. J Rheumatol. 1994;21(7):1227–37.PubMed
13.
Kushner I, Rzewnicki D, Samols D. What does minor elevation of C-reactive protein signify? Am J Med. 2006;119(2):166. e117-128.CrossRefPubMed
14.
Matsui T, Kuga Y, Kaneko A, Nishino J, Eto Y, Chiba N, et al. Disease Activity Score 28 (DAS28) using C-reactive protein underestimates disease activity and overestimates EULAR response criteria compared with DAS28 using erythrocyte sedimentation rate in a large observational cohort of rheumatoid arthritis patients in Japan. Ann Rheum Dis. 2007;66(9):1221–6.CrossRefPubMedPubMedCentral
15.
Inoue E, Yamanaka H, Hara M, Tomatsu T, Kamatani N. Comparison of Disease Activity Score (DAS)28- erythrocyte sedimentation rate and DAS28- C-reactive protein threshold values. Ann Rheum Dis. 2007;66(3):407–9.CrossRefPubMedPubMedCentral
16.
Connolly M, Veale DJ, Fearon U. Acute serum amyloid A regulates cytoskeletal rearrangement, cell matrix interactions and promotes cell migration in rheumatoid arthritis. Ann Rheum Dis. 2011;70(7):1296–303.CrossRefPubMed
17.
Kosuge M, Ebina T, Ishikawa T, Hibi K, Tsukahara K, Okuda J, et al. Serum amyloid A is a better predictor of clinical outcomes than C-reactive protein in non-ST-segment elevation acute coronary syndromes. Circ J. 2007;71(2):186–90.CrossRefPubMed
18.
Simic-Ogrizovic S, Dopsaj V, Bogavac-Stanojevic N, Obradovic I, Stosovic M, Radovic M. Serum amyloid-A rather than C-reactive protein is a better predictor of mortality in hemodialysis patients. Tohoku J Exp Med. 2009;219(2):121–7.CrossRefPubMed
19.
Mayer JM, Raraty M, Slavin J, Kemppainen E, Fitzpatrick J, Hietaranta A, et al. Serum amyloid A is a better early predictor of severity than C-reactive protein in acute pancreatitis. Br J Surg. 2002;89(2):163–71.CrossRefPubMed
20.
von Hutten H, Mihatsch M, Lobeck H, Rudolph B, Eriksson M, Rocken C. Prevalence and origin of amyloid in kidney biopsies. Am J Surg Pathol. 2009;33(8):1198–205.CrossRef
21.
Cunnane G, Grehan S, Geoghegan S, McCormack C, Shields D, Whitehead AS, et al. Serum amyloid A in the assessment of early inflammatory arthritis. J Rheumatol. 2000;27(1):58–63.PubMed
22.
Visvanathan S, Wagner C, Rojas J, Kay J, Dasgupta B, Matteson EL, et al. E-selectin, interleukin 18, serum amyloid a, and matrix metalloproteinase 9 are associated with clinical response to golimumab plus methotrexate in patients with active rheumatoid arthritis despite methotrexate therapy. J Rheumatol. 2009;36(7):1371–9.CrossRefPubMed
23.
Targonska-Stepniak B, Dryglewska M, Majdan M. Influence of long-term leflunomide treatment on serum amyloid concentration in rheumatoid arthritis patients. Pharmacol Rep. 2010;62(4):719–25.CrossRefPubMed
24.
Targonska-Stepniak B, Majdan M. Serum amyloid A as a marker of persistent inflammation and an indicator of cardiovascular and renal involvement in patients with rheumatoid arthritis. Mediators Inflamm. 2014;2014:793628.CrossRefPubMedPubMedCentral
25.
Shen C, Sun XG, Liu N, Mu Y, Hong CC, Wei W, et al. Increased serum amyloid A and its association with autoantibodies, acute phase reactants and disease activity in patients with rheumatoid arthritis. Mol Med Rep. 2015;11(2):1528–34.PubMed
26.
Moreland LW, O'Dell JR, Paulus HE, Curtis JR, Bathon JM, St Clair EW, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64(9):2824–35.CrossRefPubMedPubMedCentral
27.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24.CrossRefPubMed
28.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham 3rd CO, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol. 2010;62(9):2569–81.CrossRef
29.
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon 3rd RO, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107(3):499–511.CrossRefPubMed
30.
Navarro-Millan I, Charles-Schoeman C, Yang S, Bathon JM, Bridges Jr SL, Chen L, et al. Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial. Arthritis Rheum. 2013;65(6):1430–8.CrossRefPubMedPubMedCentral
31.
Aziz N, Fahey JL, Detels R, Butch AW. Analytical performance of a highly sensitive C-reactive protein-based immunoassay and the effects of laboratory variables on levels of protein in blood. Clin Diagn Lab Immunol. 2003;10(4):652–7.PubMedPubMedCentral
32.
Poole S, Walker D, Gaines Das RE, Gallimore JR, Pepys MB. The first international standard for serum amyloid A protein (SAA). Evaluation in an international collaborative study. J Immunol Methods. 1998;214(1-2):1–10.CrossRefPubMed
33.
Migita K, Izumi Y, Jiuchi Y, Kozuru H, Kawahara C, Izumi M, et al. Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis. Clin Exp Immunol. 2014;175(2):208–14.CrossRefPubMedPubMedCentral
34.
Christensen MB, Langhorn R, Goddard A, Andreasen EB, Moldal E, Tvarijonaviciute A, et al. Comparison of serum amyloid A and C-reactive protein as diagnostic markers of systemic inflammation in dogs. Can Vet J. 2014;55(2):161–8.PubMedPubMedCentral
35.
Ally MM, Hodkinson B, Meyer PW, Musenge E, Tikly M, Anderson R. Serum matrix metalloproteinase-3 in comparison with acute phase proteins as a marker of disease activity and radiographic damage in early rheumatoid arthritis. Mediators Inflamm. 2013;2013:183653.CrossRefPubMedPubMedCentral
36.
Eklund KK, Niemi K, Kovanen PT. Immune functions of serum amyloid A. Crit Rev Immunol. 2012;32(4):335–48.CrossRefPubMed
37.
Takata S, Wada H, Tamura M, Koide T, Higaki M, Mikura SI, Yasutake T, Hirao S, Nakamura M, Honda K et al. Kinetics of c-reactive protein (CRP) and serum amyloid A protein (SAA) in patients with community-acquired pneumonia (CAP), as presented with biologic half-life times. Biomarkers. 2011;16(6):530–535.
38.
Connolly M, Mullan RH, McCormick J, Matthews C, Sullivan O, Kennedy A, et al. Acute-phase serum amyloid A regulates tumor necrosis factor alpha and matrix turnover and predicts disease progression in patients with inflammatory arthritis before and after biologic therapy. Arthritis Rheum. 2012;64(4):1035–45.CrossRefPubMed
39.
Migita K, Koga T, Torigoshi T, Motokawa S, Maeda Y, Jiuchi Y, et al. Induction of interleukin-23 p19 by serum amyloid A (SAA) in rheumatoid synoviocytes. Clin Exp Immunol. 2010;162(2):244–50.CrossRefPubMedPubMedCentral
40.
Satomura K, Torigoshi T, Koga T, Maeda Y, Izumi Y, Jiuchi Y, et al. Serum amyloid A (SAA) induces pentraxin 3 (PTX3) production in rheumatoid synoviocytes. Mod Rheumatol. 2013;23(1):28–35.CrossRefPubMed
41.
Connolly M, Marrelli A, Blades M, McCormick J, Maderna P, Godson C, et al. Acute serum amyloid A induces migration, angiogenesis, and inflammation in synovial cells in vitro and in a human rheumatoid arthritis/SCID mouse chimera model. J Immunol. 2010;184(11):6427–37.CrossRefPubMed
42.
Migita K, Koga T, Torigoshi T, Maeda Y, Miyashita T, Izumi Y, et al. Serum amyloid A protein stimulates CCL20 production in rheumatoid synoviocytes. Rheumatology (Oxford). 2009;48(7):741–7.CrossRef
43.
Kushner I, Jiang SL, Zhang D, Lozanski G, Samols D. Do post-transcriptional mechanisms participate in induction of C-reactive protein and serum amyloid A by IL-6 and IL-1? Ann NY Acad Sci. 1995;762:102–7.CrossRefPubMed
44.
Calero C, Arellano E, Lopez-Villalobos JL, Sanchez-Lopez V, Moreno-Mata N, Lopez-Campos JL. Differential expression of C-reactive protein and serum amyloid A in different cell types in the lung tissue of chronic obstructive pulmonary disease patients. BMC Pulm Med. 2014;14:95.CrossRefPubMedPubMedCentral
45.
de Seny D, Cobraiville G, Charlier E, Neuville S, Esser N, Malaise D, et al. Acute-phase serum amyloid a in osteoarthritis: regulatory mechanism and proinflammatory properties. PLoS One. 2013;8(6):e66769.CrossRefPubMedPubMedCentral
46.
Hensor EM, Emery P, Bingham SJ, Conaghan PG, Consortium Y. Discrepancies in categorizing rheumatoid arthritis patients by DAS-28(ESR) and DAS-28(CRP): can they be reduced? Rheumatology (Oxford). 2010;49(8):1521–9.CrossRef
47.
Bjorkman L, Raynes JG, Shah C, Karlsson A, Dahlgren C, Bylund J. The proinflammatory activity of recombinant serum amyloid A is not shared by the endogenous protein in the circulation. Arthritis Rheum. 2010;62(6):1660–5.CrossRefPubMed
48.
van den Brand B, Waterborg C, van den Berg W, van de Loo F. Is the serum amyloid A we use really serum amyloid A? Comment on the article by Connolly et al. Arthritis Rheum. 2013;65(1):283–4.CrossRefPubMed
49.
Deetman PE, Bakker SJ, Dullaart RP. High sensitive C-reactive protein and serum amyloid A are inversely related to serum bilirubin: effect-modification by metabolic syndrome. Cardiovasc Diabetol. 2013;12(1):166.CrossRefPubMedPubMedCentral
50.
Jamnitski A, Levels JH, van den Oever IA, Nurmohamed MT. High-density lipoprotein profiling changes in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: a cohort study. J Rheumatol. 2013;40(6):825–30.CrossRefPubMed
51.
Hatanaka E, Dermargos A, Armelin HA, Curi R, Campa A. Serum amyloid A induces reactive oxygen species (ROS) production and proliferation of fibroblast. Clin Exp Immunol. 2011;163(3):362–7.CrossRefPubMedPubMedCentral
52.
Nadeem N, Woodside JV, Neville CE, McCall DO, McCance D, Edgar D, et al. Serum amyloid A-related inflammation is lowered by increased fruit and vegetable intake, while high-sensitive C-reactive protein, IL-6 and E-selectin remain unresponsive. Br J Nutr. 2014;112(7):1129–36.CrossRefPubMed
Metadata
Title
Differential response of serum amyloid A to different therapies in early rheumatoid arthritis and its potential value as a disease activity biomarker
Authors
Yong Gil Hwang
Goundappa K. Balasubramani
Ilinca D. Metes
Marc C. Levesque
S. Louis Bridges Jr.
Larry W. Moreland
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2016
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-016-1009-y

Other articles of this Issue 1/2016

Arthritis Research & Therapy 1/2016 Go to the issue

Research article

Initial combination therapy versus step-up therapy in treatment to the target of remission in daily clinical practice in early rheumatoid arthritis patients: results from the DREAM registry

Research article

S100A8/A9, a potent serum and molecular imaging biomarker for synovial inflammation and joint destruction in seronegative experimental arthritis

Research article

Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study

Research article

Tumor necrosis factor alpha, citrullination, and peptidylarginine deiminase 4 in lung and joint inflammation

Review

Lymphatic imaging to assess rheumatoid flare: mechanistic insights and biomarker potential

Research article

Changes in resting state functional connectivity after repetitive transcranial direct current stimulation applied to motor cortex in fibromyalgia patients
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits