Prevalence, significance and predictive value of antiphospholipid antibodies in Crohn’s disease

Table 1 Prevalence and clinical significance of antiphospholipid antibodies in inflammatory bowel disease - review of the literature

Ref.	Study design	Group	n	ACA prevalence (%)				Anti-β2-GPI prevalence (%)				ACA						Anti-β2-GPI
				Total	IgG	IgM	IgA	Total	IgG	IgM	IgA	Disease activity	Association with disease phenotype			TE event	IS therapy	Disease activity	Association with disease phenotype			TE event	IS therapy
													Location	Complicated disease behaviour	Need for surgery				Location	Complicated disease behaviour	Need for surgery
[19]	R	HC	136		4.0
		CD	73		20.0							No	No		No	No	No
		UC	63		10.0							No	No		No	No	No
[20]	P	AS	19		5.3	5.3		0	0	0
		CD	63		8.0	3.0		0	0	0		No						No
[21]	CS	CD	22	36.0								No	No
		UC	30	20.0								No	No
[22]	CS	CD	50	22.0	10.0	6.0	6					No	No			No	No
[23]	R	HC	40		5.0
		CD	41		26.8							No				No
		UC	19		26.3							No				No
[24]	CS	HC	261		1.2	1.2
		UC	80		10.0	17.5						No	No			No	No
[25]	R&CS	HC	100	3.0	2.0	1.0		0	0	0
		CD	45	15.6	8.9	6.7		4.4	2.2	2.2		No	No	No		No	No	No	No	No		No	No
		UC	83	18.1	13.3	4.8		10.8	8.4	2.4		+	No			No	No	No	No			No	No
[26]	CS	HC	118		2.5
		CD	138		11.0							No				No	No
[27]	CS	HC	40
		CD	7		3.9	0
		UC	19
[28]	P	CD	4	0												No
		UC	8	12.5
[29]	R	HC	102
		CD	24	6.6												No
		UC	21
[30]	R	HC	53	0	0
		CD	29	9.4	6.9
		UC	24		12.5
[31]	R	HC	100
		CD	26	0	0
		UC	75	1.3	1.3
[32]	CS	IBD	20	30.0
[33]	CS	HC	27	0	0
		CD	5	7.4	3.7
		UC	22

ACA: Anti-cardiolipin antibody; β2-GPI: β2-Glycoprotein-I; CS: Cross-sectional; P: Prospective; R: Retrospective; TE: Thromboembolic; HC: Healthy control; CD: Crohn’s disease; UC: Ulcerative colitis; IS: Immunosuppressive.

Table 2 Clinical characteristics of inflammatory bowel disease patients at time of inclusion n (%)

	CD		UC
	(n = 271)		(n = 187)
Male/female (n)	115/156		86/101
Age (yr)1	31 (24.0-41.0)		40 (29.0-52.0)
Age at presentation (yr)1	25 (19.0-33.0)		33 (23.0-43.0)
Duration (yr)1	4 (1.0-9.0)		4 (1.0-11.0)
Familial IBD	12 (4.4)		6 (3.2)
Location
L1	46 (17.0)	Proctitis	30 (16.0)
L2	67 (24.7)	Left-sided	104 (55.6)
L3	157 (57.9)	Extensive	53 (28.3)
L4 only	1 (0.4)
All L4	18
Behavior
B1	154 (56.5)	Remitting	174 (93.0)
B2	56 (20.7)	Continuous	12 (6.4)
B3	61 (22.5)	Prolonged remission	1 (0.5)
Perianal disease	76 (27.5)		-
Arthritis	54 (19.9)		26 (13.9)
Ocular manifestations	65 (24.0)		12 (6.4)
Cutaneous manifestation	35 (12.9)		16 (8.6)
PSC	9 (3.3)		8 (4.3)
Steroid use/refractory	242 (89.3)/32 (13.2)		144 (77.0)/11 (7.6)
Azathioprine use	196 (72.3)		66 (35.3)
Surgery/multiple in CD	54 (19.6)/19 (7.0)		7 (3.7)
Biological use	106 (39.1)		25 (13.4)
Smoking habits
never	219 (80.8)		167 (89.3)
yes	47 (17.3)		18 (9.6)
previous	5 (1.8)		2 (1.1)
Disease activity
Inactive HBI ≤ 4	199 (73.4)	Inactive partial Mayo ≤ 3	135 (72.2)
		Active partial Mayo > 4
Active HBI ≥ 5	72 (26.6)		52 (27.8)

¹Median (IQR). Location: L1: Ileal; L2: Colonic; L3: Ileocolonic; L4: Upper gastrointestinal disease; Behavior: B1: Inflammatory; B2: Stenosing; B3: Penetrating; PSC: Primary sclerosing cholangitis; Surgery: CD-related abdominal surgery and colectomy in UC; HBI: Harvey-Bradshaw Index; CD: Crohn’s disease; UC: Ulcerative colitis.

Table 3 Anti-phospholipid antibodies in patients with Crohn’s disease, ulcerative colitis, and healthy controls n (%)

	CD (n = 265)	UC (n = 186)	HC (n = 103)
Anti-β2-GPI IgG	5 (1.9)	4 (2.2)	2 (1.9)
Anti-β2-GPI IgM	8 (3.0)	12 (6.5)	3 (2.9)
Anti-β2-GPI IgA	7 (2.6)	7 (3.8)	3 (2.9)
Any anti-β2-GPI	19 (7.2)	18 (9.7)	8 (7.8)
ACA IgG	27 (10.2)bd	4 (2.2)d	2 (1.9)b
ACA IgM	8 (3.0)	4 (2.2)	1 (1.0)
ACA IgA	51 (19.2)bd	1 (0.5)d	0 (0.0)b
Any ACA	62 (23.4)bd	9 (4.8)d	3 (2.9)b
Anti-PS/PT IgG	20 (7.5)	9 (4.8)	9 (8.7)
Anti-PS/PT IgM	25 (9.4)bc	8 (4.3)c	1 (1.0)b
Anti-PS/PT IgA	24 (9.1)c	7 (3.8)c	9 (8.7)
Any anti-PS/PT	54 (20.4)d	19 (10.2)d	16 (15.5)

^bP < 0.01, CD vs controls;

^cP < 0.05,

^dP < 0.01, CD vs UC. Using χ²-test with Yates correction. APLA: Antiphospholipid antibodies; β2-GPI: Beta2-glycoprotein-I; ACA: Anti-cardiolipin antibody; PS/PT: Phosphatidylserine/prothrombin complex; CD: Crohn’s disease; UC: Ulcerative colitis.

Table 4 Antiphospholipid antibodies and clinical characteristics of complication and surgery naïve Crohn’s disease patient cohort n (%)

Factor	Follow-up of CD B1 at first sampling total cohort (n = 143)
	CD B1 total	No complication	Perianal change only (B1p)	Behaviour change to B2 or B3	No surgery	Surgery
	(n = 143)	(n = 114)	(n = 7)	(n = 22)	(n = 130)	(n = 13)
Male/female (n)	60/83	45/69	5/2	10/12	55/75	5/8
Age at presentation (yr)1	25 (19.0-34.0)	26 (20.0-34.3)	17 (14.0-31.0)	25 (18.8-34.8)	25 (19.0-34.0)	31 (18.0-35.5)
Duration (yr)1	3 (1.0-6.0)	2 (1.0-7.0)	3 (1.0-5.0)	3 (1.0-5.0)	2 (1.0-6.0)	3 (1.0-10.0)
Location
L1	30 (21.0)	24 (21.1)	0 (0.0)	6 (27.3)	26 (20.0)	4 (30.8)
L2	51 (35.7)	44 (38.6)	3 (42.9)	4 (18.2)	48 (36.9)	3 (23.1)
L3	62 (43.3)	46 (40.4)	4 (57.1)	12 (54.5)	56 (43.1)	6 (46.2)
L4 only	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Frequent relapse	27 (18.9)	18 (15.8)2	4 (57.1)2	5 (22.7)	23 (17.7)	4 (30.8)
Smoking habit yes	21 (16.2)	14 (12.3)2	2 (28.6)	8 (36.4)2	21 (16.2)	3 (23.1)
Follow up time from first sampling, mo1	53.4 (38.0-79.3)	51.7 (36.9-73.9)	79.8 (42.9-91.4)	64.7 (45.6-85.0)	50.93 (37.25-74.2)	84.03 (60.0-91.7)
Positive markers
Anti-β2-GPI IgG	1.4	1.8	0	0	1.6	0
Anti-β2-GPI IgM	5.0	5.3	16.7	0	5.5	0
Anti-β2-GPI IgA	2.8	1.8	16.7	4.5	3.1	0
Any anti-β2-GPI	8.5	8.8	16.7	4.5	9.4	0
ACA IgG	9.2	11.5	0	0	10.2	0
ACA IgM	2.8	3.5	0	0	3.1	0
ACA IgA	17.0	18.6	33.3	4.5	18.8	0
Any ACA	19.9	22.1	33.3	4.5	21.9	0
Anti-PS/PT IgG	8.5	8.0	0	13.6	7.8	15.4
Anti-PS/PT IgM	7.8	8.8	16.7	0	7.8	7.7
Anti-PS/PT IgA	9.9	9.7	16.7	9.1	10.9	0
Any anti-PS/PT	20.6	19.5	33.3	22.7	20.3	23.1

¹Median (IQR);

²Using χ²-test with Yates correction (P≤ 0.01);

³Using Mann-Whitney test (P < 0.01). Location: L1: Ileal; L2: Colonic; L3: Ileocolonic; L4: Upper gastrointestinal disease; Behavior: B1: Inflammatory; B2: Stenosing; B3: Penetrating. APLA: Antiphospholipid antibodies; β2-GPI: Beta2-glycoprotein-I; ACA: Anti-cardiolipin antibody; PS/PT: Phosphatidylserine/prothrombin complex; CD: Crohn’s disease.

Table 5 Univariate Kaplan Meier and Log-rank analysis of serologic and clinical factor associated with complicated disease course in B1 Crohn’s disease patients (n = 143)

Variable	Internal penetrating and/or stricturing complication		Perianal penetrating complication		CD-related abdominal surgery
	HR (95%CI)	PLogRank-value	HR (95%CI)	PLogRank-value	HR (95%CI)	PLogRank-value
Gender - male	1.10 (0.47-2.55)	0.83	2.69 (0.80-9.03)	0.11	0.91 (0.33-2.55)	0.86
Smoking	3.72 (1.23-11.21)1	0.021	1.61 (0.36-7.19)	0.53	1.64 (0.45-5.97)	0.45
Location (colon only)	0.41 (0.17-0.96)1	0.041	1.00 (0.29-3.43)	0.99	0.61 (0.22-1.74)	0.36
Frequent relapse	1.10 (0.39-3.07)	0.85	7.29 (1.72-30.99)1	0.0071	1.64 (0.44-6.10)	0.46
APLA at all	1.36 (0.59-3.16)	0.47	1.30 (0.40-4.27)	0.66	1.37 (0.49-3.80)	0.55
Anti-β2-GPI at all	0.56 (0.13-2.32)	0.42	0.99 (0.13-7.70)	0.99	0.33 (0.06-1.81)	0.20
ACA at all	0.41 (0.13-1.26)	0.12	1.12 (0.23-5.49)	0.89	0.30 (0.07-1.27)	0.10
Anti-PS/PT at all	1.07 (0.39-2.97)	0.89	1.74 (0.38-8.03)	0.48	1.11 (0.29-4.18)	0.88

¹The P_LogRank-value < 0.05. APLA: Antiphospholipid antibodies; β2-GPI: Beta2-glycoprotein-I; ACA: Anti-cardiolipin antibody; PS/PT: Phosphatidylserine/prothrombin complex.

Table 6 Antiphospholipid antibodies, thrombophilia markers and clinical characteristics of total Crohn’s disease according to presence and type of thrombosis n (%)

Factor	Follow-up of CD Total Cohort from diagnosis (n = 265)
	No thrombosis	Arterial thrombosis	Venous thrombosis	No pregnancy loss	Pregnancy loss
	(n = 251)	(n = 3)	(n = 11)	(n = 146)	(n = 10)
Male/female	104/147	1/2	7/4	146/0	10/0
Age at presentation (yr)1	25.0 (19.0-33.0)	40.0 (28.0-42.0)	29.5 (23.3-39.3)	26.0 (20.0-35.0)	25.5 (21.0-35.0)
Frequent relapse	48 (20.2)	0 (0.0)	4 (36.4)	33 (24.1)	2 (20.0)
Previous thrombosis	1 (0.4)3	0 (0.0)	4 (36.4)3	2 (1.4)	0 (0.0)
Smoking habits yes	48 (19.1)	0 (0.0)	3 (27.3)	22 (15.1)	2 (20.0)
Follow up time from diagnosis, mo1	102.2 (63.3-172.8)2	149.9 (130.8-219.8)	186.3 (142.0-244.2)2	109.0 (61.8-184.6)	136.5 (95.4-180.6)
Positive markers (%)
Anti-β2-GPI IgG and/or IgM	4.8	0	9.1	4.9	10
Anti-β2-GPI IgA	2.8	0	0	4.9	0
ACA IgG and/or IgM	12.1	0	27.3	13.9	10
ACA IgA	19.0	66.7	0	20.1	10
Anti-PS/PT IgG and/or IgM	14.6	50.0	36.4	18.3	40
Anti-PS/PT IgA	8.9	50.0	9.1	7.7	10
At least 1 APLA pos	48.0	66.7	54.5	52.8	60
At least 2 APLA pos	16.1	33.3	9.1	18.1	10
At least 3 APLA pos	3.2	0	9.1	4.9	0
Thrombophilia markers3 (%)
LA	7.5	0	0	5.1	0
PS deficiency (inherited and/or acquired)	8.1	0	25.0	12.7	0
ATIII deficiency (inherited and/or acquired)	0	0	0	0	0
PC deficiency (inherited and/or acquired)	3.0	0	0	4.8	0
FV Leiden	5.94	0	42.94	7.8	0
FII20210A	5.9	0	16.7	7.8	0

¹Median (IQR);

²Using Kruskal-Wallis test (P≤ 0.01);

³Using χ²-test with Yates correction (P≤ 0.05);

⁴Serologic and genetic markers of thrombophilia were available in 105 patients. pts: Patients; APLA: Antiphospholipid antibodies; β2-GPI: Beta2-glycoprotein-I; ACA: Anti-cardiolipin antibody; PS/PT: Phosphatidylserine/prothrombin complex.

Table 7 Stability of antiphospholipid antibodies marker status over time in inflammatory bowel diseases patients with at least 2 samples during the disease course n (%)

APLA marker	CD (n = 198)	UC (n = 103)
Anti-β2-GPI IgG
Stable negative	194 (98.0)	97 (94.2)
Stable positive	1 (0.5)	2 (1.9)
Neg. to pos.	0 (0.0)	3 (2.9)
Pos. to neg.	3 (1.5)	1 (1.0)
Anti-β2-GPI IgM
Stable negative	186 (94.0)	94 (91.3)
Stable positive	4 (2.0)	3 (2.9)
Neg. to pos.	6 (3.0)	5 (4.9)
Pos. to neg.	2 (1.0)	1 (0.9)
Anti-β2-GPI IgA
Stable negative	190 (96.0)	93 (90.3)
Stable positive	1 (0.5)	4 (3.9)
Neg. to pos.	3 (1.5)	5 (4.9)
Pos. to neg.	4 (2.0)	1 (0.9)
ACA IgG
Stable negative	139 (70.2)	95 (92.2)
Stable positive	3 (1.5)	1 (1.0)
Neg. to pos.	42 (21.2)	6 (5.8)
Pos. to neg.	14 (7.1)	1 (1.0)
ACA IgM
Stable negative	173 (87.4)	95 (92.2)
Stable positive	3 (1.5)	1 (1.0)
Neg. to pos.	18 (9.1)	7 (6.8)
Pos. to neg.	4 (2.0)	0 (0.0)
ACA IgA
Stable negative	73 (36.9)	78 (75.7)
Stable positive	13 (6.6)	0 (0.0)
Neg. to pos.	93 (46.9)	24 (23.3)
Pos. to neg.	19 (9.6)	1 (1.0)

Anti-PS/PT measurements were only preformed on the first available serum samples of the patients. APLA: Antiphospholipid antibodies; β2-GPI: Beta2-glycoprotein-I; ACA: Anti-cardiolipin antibody; PS/PT: Phosphatidylserine/prothrombin complex; CD: Crohn’s disease; UC: Ulcerative colitis.