Serum Calprotectin: A Promising Biomarker in Rheumatoid Arthritis and Axial Spondyloarthritis

Matthias Jarlborg; Delphine S. Courvoisier; Céline Lamacchia; Laura Martinez Prat; Michael Mahler; Chelsea Bentow; Axel Finckh; Cem Gabay; Michael J. Nissen

Disclosures

Arthritis Res Ther. 2020;22(105)

Abstract and Introduction

Abstract

Background: Calprotectin (S100A8/S100A9 protein) is known as a damage-associated molecular pattern (DAMP) protein and reflects mainly neutrophil activation. Serum calprotectin levels might be a good alternative to acute-phase protein as a biomarker in inflammatory rheumatic diseases. The aim of this study is to investigate the association of serum calprotectin with disease activity and severity in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA).

Methods: Serum calprotectin was measured in patients with RA, axSpA, and PsA from the prospective Swiss Clinical Quality Management (SCQM) registry. Asymptomatic first-degree relatives of RA patients were used as healthy controls (HC). Outcomes included swollen joint count (SJC), Disease Activity Score (DAS), Health Assessment questionnaire (HAQ), joint radiographs, and ultrasound power Doppler (USPD) score for RA; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS) and coxitis for axSpA; and SJC and Disease Activity Index for PSoriatic Arthritis (DAPSA) for PsA. Comparison of outcomes by calprotectin quartile levels was performed using Kruskal-Wallis tests for continuous outcomes or trend tests for categorical outcomes.

Results: A total of 1729 subjects [RA = 969, axSpA = 451, PsA = 237, and HC = 72] were included. Median levels of serum calprotectin were higher in each disease group compared to HC (p < 0.01). In RA patients, all clinical outcomes were statistically different between quartiles of serum calprotectin, indicating an association between calprotectin levels and higher disease activity (SJC, DAS, and USPD scores) and severity (joint radiographs and HAQ). In axSpA, an association between calprotectin levels and ASDAS score (p < 0.01) and prevalence of coxitis (p = 0.02) was observed. For PsA patients, SJC and DAPSA did not differ across calprotectin quartiles.

Conclusions: This large study supports the association of serum calprotectin levels with disease activity in both RA and axSpA, but not in PsA.

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Arthritis Res Ther. 2020;22(105) © 2020 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Abstract and Introduction
Background
Methods
Results
Discussion
Conclusions
References

Table 1. Population characteristics and median serum calprotectin levels in each group. All results are mean (with standard deviation), except those with an asterisk* which are median [with interquartile range] and those marked with a " ^§" which are number of patients (%). *Abbreviations*: *BMI* body mass index, *CRP* C-reactive protein, *ESR* erythrocyte sedimentation rate, *GCS* glucocorticoids, *cDMARDS* conventional disease-modifying anti-rheumatic drugs, *bDMARDS* biological disease-modifying anti-rheumatic drugs, *TNFi* TNF inhibitors
	Rheumatoid arthritis	Axial spondyloarthritis	Psoriatic arthritis	Healthy control	p value
n	969	451	237	72
Gender = male^§	250 (25.8)	268 (59.4)	136 (57.4)	13 (18.1)	< 0.01
Age, year	57.6 (13.2)	44.0 (12.3)	51.5 (12.2)	56.5 (8.3)	< 0.01
Disease duration, year	10.9 (10.1)	9.9 (9.8)	7.9 (8.4)	–	< 0.01
BMI kg/m²	26.2 (5.4)	26.0 (4.9)	27.5 (5.4)	24.1 (3.4)	< 0.01
Smoker^§	435/758 (57.4)	146/264 (55.3)	101/168 (60.1)	34/72 (47.2)	0.37
Calprotectin μg/ml*	2.6 [1.7, 4.3]	2.4 [1.6, 3.9]	2.2 [1.4, 3.4]	1.2 [0.8, 2.0]	< 0.01
CRP mg/l*	3.0 [1.0, 7.9]	3.0 [1.0, 8.0]	3.0 [1.0, 7.9]	–	0.39
ESR mm/h*	12.0 [6.0, 22.0]	8.0 [4.0, 17.0]	8.0 [3.0, 14.0]	–	0.62
Swollen joint count*	1.0 [0.0, 3.0]	0.0 [0.0, 0.0]	0.0 [0.0, 2.0]	–	< 0.01
Disease activity score¹	2.8 [2.0, 3.9]	2.3 [1.5, 3.2]	12 [5.1, 24.0]		–
Patients on GCS^§	277 (28.6)	3 (0.7)	19 (8.0)	–	< 0.01
Patients on cDMARDS^§	645 (66.6)	75 (16.6)	142 (59.9)	–	< 0.01
Patients on bDMARDS^§	557 (57.5)	184 (40.8)	108 (45.6)	–	< 0.01
TNFi^§	205 (21.2)	180 (39.9)	100 (42.2)		< 0.01
Tocilizumab^§	92 (9.5)	3 (0.7)	3 (1.3)		< 0.01
Rituximab^§	172 (17.8)	0 (0.0)	1 (0.4)		< 0.01

¹Composite scores: DAS28-ESR for RA, ASDAS-CRP for AxSpA, and DAPSA for PsA are presented

Table 2. Characteristics of the patients with rheumatoid arthritis stratified by calprotectin percentiles. All results are mean (with standard deviation), except those with an asterisk* which are median [with interquartile range] and those marked with a " ^§" which are number of patients (%). *Abbreviations*: *BMI* body mass index, *CRP* C-reactive protein, *ESR* erythrocyte sedimentation rate, *RADAI* Rheumatoid Arthritis Disease Activity Index, *HAQ* Health Assessment Questionnaire, *CDAI* Clinical Disease Activity Index, *DAS28* 28-joints Disease Activity Score, US ultrasound, *SONAR* Swiss Sonography in Arthritis and Rheumatism, *ACR/EULAR* American College of Rheumatology/European League Against Rheumatism, RF rheumatoid factor, *ACPA* anti-citrullinated peptide antibodies
Serum calprotectin quartile [μg/ml]	0–1.7	1.7–2.6	2.6–4.3	4.3–13	p value
n	243	242	242	242
Age years	56.6 (13.0)	57.2 (13.0)	58.3 (13.8)	58.3 (12.8)	0.41
Elderly onset^§1	38 (15.6)	51 (21.1)	45 (18.6)	43 (17.8)	0.77
Disease duration, years	10.6 (10.1)	10.8 (10.0)	10.8 (10.0)	11.3 (10.5)	0.92
Gender = male^§	53 (21.8)	56 (21.3)	65 (26.9)	76 (31.4)	0.01
BMI kg/m²	25.3 (5.0)	26.3 (5.5)	26.3 (5.9)	27.0 (5.2)	0.16
CRP mg/l*	2.0 [1.0, 4.6]	2.0 [1.0, 7.0]	2.2 [1.0, 7.0]	4.2 [2.0, 12.0]	< 0.01
ESR mm/h*	8.0 [5.0, 16.0]	10.0 [6.0, 20.0]	12.0 [5.5, 22.5]	16.0 [8.0, 30.0]	< 0.01
Tender joint count	2.6 (4.3)	3.2 (4.8)	3.6 (5.2)	4.0 (5.6)	0.02
Swollen joint count	1.3 (2.5)	1.7 (2.8)	2.2 (3.3)	3.4 (4.5)	< 0.01
RADAI score	2.3 (1.8)	2.9 (2.2)	2.9 (2.2)	3.3 (2.2)	< 0.01
HAQ	0.6 (0.6)	0.8 (0.7)	0.8 (0.7)	1.0 (0.7)	< 0.01
CDAI	7.3 (7.9)	9.8 (9.9)	11.2 (11.7)	12.3 (13.4)	< 0.01
DAS28 CRP	2.5 (1.0)	2.8 (1.1)	2.8 (1.2)	3.2 (1.4)	< 0.01
DAS28 ESR	2.6 (1.3)	2.9 (1.3)	3.0 (1.3)	3.5 (1.5)	< 0.01
DAS28 ESR moderate/high^§2	58/190 (30.5)	78/196 (39.8)	83/193 (43.09)	118/200 (59.0)	< 0.01
DAS28 ESR remission ^§3	103/190 (54.2)	86/196 (43.9)	78/193 (40.4)	60/200 (30.0)	< 0.01
US score B mode score	8.9 (6.5)	9.1 (6.3)	10.4 (5.3)	11.6 (8.7)	0.13
US Power Doppler score	2.2 (5.9)	2.0 (4.0)	2.0 (3.0)	4.7 (6.1)	0.01
SONAR positive^§	28/44 (63.6)	30/47 (63.8)	31/47 (66.0)	58/71 (81.7)	0.02
ACR/EULAR 2010 Criteria	6.7 (2.1)	7.1 (2.1)	7.3 (2.2)	7.6 (2.1)	< 0.01
RF positive^§	157/232 (67.7)	164/233 (70.4)	172/228 (75.4)	179/236 (75.8)	0.02
ACPA positive^§	144/226 (63.7)	145/223 (65.0)	158/217 (72.8)	159/227 (70.0)	0.06
Rheumatoid nodules^§	36/232 (15.5)	51/232 (21.9)	46/226 (20.3)	59/223 (26.4)	0.01

¹Elderly onset = age of onset after 60 years of age
²Proportion of patients with a DAS28 ESR ≥ 3.2
³Proportion of patients with a DAS28 ESR < 2.6

Table 3. Characteristics of the patients with axial spondyloarthritis stratified by calprotectin percentiles. All results are mean (with standard deviation), except those with an asterisk* which are median [with interquartile range], and those marked with a " ^§" which are number of patients (%). *Abbreviations*: *BMI* body mass index, *CRP* C-reactive protein, *ESR* erythrocyte sedimentation rate, *BASDAI* Bath Ankylosing Spondylitis Disease Activity Index, *BASFI* Bath Ankylosing Spondylitis Functional Index, *ASDAS* Ankylosing Spondylitis Disease Activity Score
Serum calprotectin quartile [μg/ml]	0–1.6	1.6–2.4	2.4–3.9	3.9–13	p value
n	113	113	112	113
Disease duration, years	10.4 (10.2)	8.5 (9.8)	9.9 (9.8)	10.6 (9.4)	0.37
Age years	45.9 (11.4)	44.4 (12.7)	43.0 (11.3)	42.7 (13.7)	0.20
Gender = male^§	62 (54.9)	62 (54.9)	67 (59.8)	77 (68.1)	0.03
BMI kg/m²	25.3 (4.7)	26.3 (4.8)	26.3 (5.4)	26.3 (4.7)	0.44
ESR mm/h*	6.0 [4.0, 11.5]	8.0 [4.0, 17.5]	8.0 [4.0, 16.0]	10.0 [4.0, 25.0]	0.01
CRP mg/l*	3.0 [1.0, 8.0]	2.0 [1.0, 8.0]	3.0 [1.0, 8.0]	4.0 [2.0, 13.0]	< 0.01
BASDAI score	3.6 (2.3)	4.0 (2.4)	3.5 (2.4)	4.1 (2.3)	0.19
BASFI score	2.1 (2.3)	2.7 (2.6)	2.3 (2.3)	2.8 (2.5)	0.22
ASDAS score	2.1 (0.9)	2.4 (1.0)	2.2 (1.1)	2.7 (1.0)	0.01
ASDAS moderate/high^§1	40/79 (50.6)	47/81 (58.0)	37/65 (56.9)	49/72 (68.1)	0.04
ASDAS remission^§2	14/79 (17.7)	16/81 (19.8)	20/65 (30.8)	4/72 (5.56)	0.20
Physician global disease activity	1.9 (1.6)	2.4 (2.0)	2.2 (2.0)	2.6 (1.8)	0.02
Swollen joint count	0.4 (0.9)	0.6 (1.8)	0.4 (0.9)	0.3 (1.2)	0.46
Hip involvement^§	3 (2.7)	3 (2.7)	5 (4.5)	10 (8.8)	0.02
Enthesitis^§	32 (28.3)	38 (33.6)	40 (35.7)	36 (31.9)	0.68
Dactylitis^§	2 (1.8)	0 (0.0)	5 (4.5)	3 (2.7)	0.51

¹Proportion of patients with an ASDAS score ≥ 2.1
²Proportion of patients with an ASDAS score < 1.3

Table 4. Characteristics of the patients with psoriatic arthritis stratified by calprotectin percentiles. All results are mean (with standard deviation), except those with an asterisk* which are median [with interquartile range] and those marked with a " ^§" which are number of patients (%). *Abbreviations*: *BMI* body mass index, *CRP* C-reactive protein, *ESR* erythrocyte sedimentation rate, *DAPSA* disease activity in psoriatic arthritis (< 15: low, 15–28: moderate, > 28 high disease activity), *DLQI* Dermatology Life Quality Index
Serum calprotectin quartile [μg/ml]	0–1.4	1.2–2.2	2.2–3.4	3.4–12	p value
n	60	59	59	59
Disease duration, years	8.3 (8.7)	8.6 (8.3)	7.5 (8.7)	7.4 (7.9)	0.84
Age years	53.6 (12.5)	50.1 (11.1)	49.8 (12.8)	52.4 (12.4)	0.27
Gender = male^§	37 (61.7)	39 (66.1)	34 (57.6)	26 (44.1)	0.04
BMI kg/m²	27.4 (4.9)	27.7 (5.2)	26.0 (4.6)	28.8 (6.7)	0.19
ESR mm/h*	6.0 [2.0, 12.0]	7.0 [2.0, 13.0]	8.0 [4.0, 12.0]	11.0 [6.0, 20.0]	0.01
CRP mg/l*	3.0 [1.0, 8.0]	2.5 [1.0, 8.0]	3.0 [1.0, 6.8]	3.4 [1.8, 7.8]	0.38
Tender joint count	3.9 (9.3)	3.3 (6.4)	4.1 (8.9)	4.8 (8.5)	0.84
Swollen joint count	1.8 (4.5)	1.3 (2.5)	1.1 (2.5)	2.2 (4.4)	0.33
DAPSA	18.2 (23.5)	15.6 (17.5)	18.4 (16.8)	21.1 (24.2)	0.80
DAPSA moderate/high^§1	14/36 (38.9)	12/39 (30.8)	14/31 (45.2)	13/28 (46.4)	0.35
DAPSA remission^§2	6/36 (16.7)	9/39 (23.1)	7/31 (22.6)	4/28 (14.3)	0.86
DLQI	3.2 (5.1)	3.0 (4.5)	4.5 (5.5)	4.6 (7.3)	0.44
Reported skin manifestation^§	14/43 (32.6)	22/39 (56.4)	23/47 (48.9)	23/38 (60.5)	0.01