Serum Levels of Beta-2 Microglobulin in Rheumatoid Arthritis Patients and its Relationship with Disease Activity: Can it be used as a Disease Activity Marker?

Key words

beta 2 microglobulin - rheumatoid arthritis - ankylosing spondylitis

Schlüsselwörter

Beta-2-Mikroglobulin - Rheumatoide Arthritis - Spondylitis ankylosans

Introduction

Rheumatoid arthritis, is a systemic chronic autoimmune disease which is characterized by inflammatory synovitis in peripheral joints [1]. In the pathogenesis of RA, the activation of CD4+ T lymphocytes plays a key role [2]. As a result, organized proinflammatory cytokine secretion managed by T and B lymphocytes has a regulatory role in the pathophysiology of RA [1]. The synovial membranes of RA patients are infiltrated with activated T lymphocytes, B lymphocytes, plasma cells, macrophages and mast cells [2] .

Beta-2 microglobulin is a low molecular weight (11 800 Dalton) protein which is synthesized in all nucleated cells including lymphocytes and macrophages and constitutes the light-chain subunit of the class 1 human leucocyte antigen (HLA) [3] [4]. The duty of β2M is to stabilize the major histocompatibility complex-1 (MHC 1) on the cell membrane, to protect the native structure of its heavy chain and also it provides high affinity antigenic peptide bindings [5]. It is found in small amounts in biological fluids such as serum, urine, colostrum, saliva, amniotic fluid and synovial fluid [6] [7]. During the continuous turnover of HLA molecules, β2M gets into the blood by sheding from the cell membrane and forms the serum free β2M [8]. Especially lymphocyte and monocyte surfaces are rich in β2M, and the main sources of serum free β2M are activated T and B lymphocytes [7] [9]. As it is a protein with low molecular weight, it is easily filtered from the glomerular basal membrane in the kidneys, but 99% of the filtered β2M is reabsorbed in the proximal tubules by endocytosis [7] [10]. Serum β2M levels are independent of sex and body mass, but they are mildly higher in the elderly due to the decreased glomerular filtration rate (GFR) [10]. As the main sources of serum β2M are lymphocytes, the serum levels increase in lymphoproliferative and autoimmune diseases where the T and B lymphocyte activity increases [9]. Increased serum β2M levels have been shown in autoimmune diseases [4] [11] [12] [13].

The aim of this study is to investigate the serum β2M levels in rheumatoid arthritis patients and its relationship with disease activity.

Material and Methods

Patients and Study Design

One hundred and thirty-seven RA, 102 Ankylosing Spondylitis (AS) and 50 healthy controls (HC) followed in the Rheumatology Department of Ankara University Faculty of Medicine between April 2019 and December 2019 were recruited for this cross-sectional study. RA patients included in the study were diagnosed based on the 2010 American College of Rheumatology- European League against Rheumatism classification criteria and AS patients according to Modified New York Criteria [14] [15]. Patients with lymphoproliferative diseases, cancer, autoimmune or autoinflammatory diseases other than RA and AS, acute or chronic infections and patients with decreased glomerular filtration rate, pregnant and breastfeeding patients were excluded from the study. The data collection at baseline included demographic characteristics, symptom duration, the tender and swollen joint count on 28 joints (TJC28, SJC28), the patient’s (Pt-VAS) and physician’s assessment of disease activity on a 0–10 cm Visual Analogue Scales (VAS), comorbidities and treatment features.

Assessment of Disease Activity

Disease activity assessment for RA patient were performed by Disease Activity Score for 28 joints with Erythrocyte Sedimentation Rate, Disease Activity Score for 28 joints with C-reactive protein (CRP), Simplified Disease Activity Score and Clinical Disease Activity Score [16] [17] [18]. As DAS28-ESR is a widely accepted index for RA studies, we classified RA patients into 2 groups as follows: remission and low disease activity group with DAS28-ESR<3.2 and moderate to high disease activity group with DAS28-ESR≥3.2

In order to evaluate disease activity in Ankylosing Spondylitis patients Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score-CRP (ASDAS-CRP) and Ankylosing Spondylitis Disease Activity Score-ESR (ASDAS-ESR) were used [19] [20] [21].

Laboratory Analysis

Routine laboratory tests such as complete blood cell count, ESR, CRP, glomerular filtration rate were investigated by using standard laboratory methods. Serum β2M levels were evaluated by turbidimethric method.

Ethical considerations

The study was approved by Ankara University Faculty of Medicine Ethics Board.

Statistical Analysis

The data was analyzed by using IBM SPSS version 21 (SPSS, Chicago,IlI). Categorical data was summarized by frequencies and percentages and quantitative data was given as means±standard deviation (SD) or medians and minimum-maximum based on their distribution. Intergroup differences were evaluated by Mann-Whitney U test. The relationship between parameters were assessed using Spearman rank correlation test. Power analyses were performed using G^*Power version 3.0.10 power and sample size calculation. A p value < 0.05 was considered statistically significant.

Results

The demographic and clinical data of the RA and AS patients and the healthy controls were summarized in [Table 1]. There was a significant age difference among the 3 groups (p<0.001). There was no significant sex difference between RA and HC (p=0.169). Serum β2M levels were significantly higher in RA patients (2.95±1.19 mg/L) when compared to both AS (2.20±0.58 mg/L) and HC (2.21±0.54) (p<0.001 and p<0.001, respectively). However, there was no statistically significant difference in serum β2M levels between AS and healthy controls (p=1.000).

Table 1 Demographic and clinical characteristics of RA, AS patients and healthy controls.

	RA	AS	Healthy Control	p
Sex, male, n (%)	28 (20.4)	65 (63.7)	15 (30.0)	<0.001
Age, years, mean (±SD)	55.1±11.2	43.4±11.9	49.8±12.2	<0.001
Diagnosis duration, median (min-max)	9 (0.1–444)	84 (1–240)	–	–
RF positivity, n (%)	84 (61.31)
ACPA positivity, n (%)	76 (55.47)
TJC, median (min-max)	1 (0–20)
SJC, median (min-max)	0 (0–10)
Comorbidities, n (%)
Hypertension	36 (26.28)
Diabetes mellitus	17 (12.41)
Hyperlipidemia	2 (1.46)
Hypothyroidism	11 (8.03)
Coronary Artery Disease	3 (2.19)
Asthma	5 (3.65)
Atrial fibrillation	1 (0.72)
Benign prostate hyperplasia	3 (2.19)
Treatment, n (%)
Corticosteroid	55 (40.14)
Hydroxychloroquine	66 (48.18)
Methotrexate	65 (47.44)
Leflunomide	38 (27.74)
Sulfasalazine	27 (19.71)
TNF-inhibitors	11 (8.03)
Tocilizumab	10 (7.29)
Rituximab	22 (16.06)
Tofacitinib	6 (4.38)
Abatacept	5 (3.65)
Disease Activity
DAS28-ESR, mean (±SD)	3.32 (±1.23)
DAS28-CRP,mean (±SD)	3.62 (±1.42)
SDAI, mean (±SD)	22.92 (±25.69)
CDAI, mean (±SD)	9.85 (±7.40)
BASDAI		2.60±1.92
BASFI		2.09±1.56
ASDAS-CRP		2.25±2.58
ASDAS-ESR		1.72±0.93
PtVAS (0–10mm)	3.26 (±2.08)	3.44±2.74
Laboratory features
ESR, mm/h, median (min-max)	21 (3–95)	8 (1–87)	11 (2–34)	<0.001
CRP, mg/L, median (min-max)	5.9 (0.1–217.0)	4.2 (0.0–144.8)	2.5 (0.1–25.2)	<0.001
White blood cell, x10 9/L, median (min-max)	7620 (2270–22930)	8515 (3980–14740)	6865 (4410–11470)	0.003
Hemoglobin, g/dL, median (min-max)	12.6±1.5	14.4±1.6	14.1±1.7	<0.001
Platelet, x10 9/L, median (min-max)	282 (120–607)	291 (158–754)	277 (168–483)	0.540
Beta-2 microglobulin, mg/L, median (min-max)	2.95±1.19	2.20±0.58	2.21±0.54	<0.001

ACPA: Anti-citrullinated peptide antibodies, CRP: C-reactive protein, ESR: Erythrocyte sedimentation rate, PtVAS: Patient-Visual Analogue Scale, RF: Rheumatoid factor, SD: Standard deviation, SJC: Swollen joint count, TJC: Tender joint count.

The RA patients were classified into 2 groups according to their disease activity based on DAS28-ESR. The serum β2M levels in the moderate to high disease activity group (DAS-28≥3.2) were significantly higher than remission and low disease activity group with DAS28-ESR<3.2 (p=0.002) ([Table 2]) ([Fig. 1]). Likewise, the ESR and CRP levels in the DAS28-ESR≥3.2 group were significantly higher than the DAS28-ESR<3.2 group (p<0.001 and p<0.01, respectively). The hemoglobin level, on the other hand, was significantly lower in the DAS28-ESR≥3.2 group (p<0.001) ([Table 2]).

Fig. 1 Beta-2 microglobulin levels of RA patients grouped according to the disease activity based on DAS28-ESR and healthy controls.

Table 2 Clinical and laboratory features of RA patients grouped according to disease activity based on DAS28-ESR.

	DAS28-ESR<3.2 (n=75)	DAS28-ESR≥3.2 (n=62)	p
Age, years, mean (±SD)	54.0±11.5	56.4±10.8	0.205
Sex, male, n (%)	19 (25.3)	9 (14.5)	0.118
Disease Duration, median (min-max)	9.5 (0.1–444.0)	8.5 (0.5–156.0)	0.608
RF positivity, n(%)	44 (58.7)	42 (67.7)	0.274
ACPA positivity, n(%)	48 (64.0)	42 (67.7)	0.646
ESR, mm/h, median, (min-max)	14 (3–50)	27 (8–95)	<0.001
CRP, mg/L, median, (min-max)	3.9 (0.1–217.0)	10.5 (0.7–158.9)	<0.001
White blood cell, × 10 9/L, median (min-max)	7030 (3100–22930)	8075 (2270–20720)	0.215
Hemoglobin, g/dL, median (min-max)	13.0±1.4	12.1±1.4	<0.001
Platelet, × 10 9/L, median (min-max)	276 (134–530)	296 (120–607)	0.057
Beta-2 microglobulin, mg/L, mean (SD)	2.67±0.87	3.30±1.42	0.002

ACPA: Anti-citrullinated peptide antibodies, CRP: C-reactive protein, ESR: Erythrocyte sedimentation rate, RF: Rheumatoid factor, SD: Standard deviation.

There were positive correlations between serum β2M levels and DAS28-ESR (r_s,0.359; p<0.001), DAS28-CRP (r_s, 0.293; p=0.001), SDAI (r_s, 0.332; p<0.001) and CDAI (r_s, 0.291; p=0.001) ([Fig. 2]). Even though there was no correlation between TJC28 and serum β2M (r_s, 3.131; p=0.334), there was statistically significant positive correlations between serum β2M and SJC28 (r_s, 0.348;p=0.009), ESR (r_s, 0.430; p<0.001₎ and CRP (r_s, 0.246; p=0.004) ([Table 3])

Fig. 2 Correlation of Beta-2 microglobulin with DAS28-ESR and DAS28-CRP in RA patients.

Table 3 Correlation of RA disease activity indices with serum Beta-2 microglobulin levels.

		Beta-2 microglobulin
DAS28-ESR	rs	0.359
	p	<0.001
DAS28-CRP	rs	0.293
	P	0.001
TJC28	rs	0.131
	P	0.334
SJC28	rs	0.348
	P	0.009
ESR	rs	0.430
	P	<0.001
CRP	rs	0.246
	p	0.004
SDAI	rs	0.332
	p	<0.001
CDAI	rs	0.291
	p	0.001

No correlations were observed between serum β2M levels and disease activity indices of AS such as ASDAS-CRP, ASDAS-ESR, BASDAI and BASFI. ([Table 4]) However, there were statistically significant positive correlations between serum β2MG levels and ESR (r_s,0.277; p=0.006) and CRP (r_s,0.297; p=0.003).

Table 4 Correlation of AS disease activity indices with serum Beta-2 microglobulin levels.

		Beta-2 microglobulin
ASDAS-CRP	rs	0.050
	p	0.622
ASDAS-ESR	rs	0.070
	p	0.492
BASDAI	rs	-0.013
	p	0.895
BASFI	rs	−0.081
	p	0.491
CRP	rs	0.297
	p	0.003
ESR	rs	0.277
	p	0.006

Elevated β2M levels were found in 76.3% of RA patients with ≥1 swollen joint count whereas elevated β2M levels were found in 51.5% of RA patients without any swollen joint (p=0.008). When the elevated CRP levels were compared, 68.4% of RA patients with ≥1 swollen joint had elevated CRP levels and 49% of RA patients without any swollen joint had elevated CRP levels (p=0.041) ([Table 5]).

Table 5 Comparison of RA patients with elevated Beta-2 microglobulin and C-reactive protein with and without swollen joint counts

	Swollen joint count<1 (n=99)	Swollen joint count ≥1 (n=38)	p value
Elevated Beta-2 microglobulin, n(%)	51 (51.5)	29 (76.3)	0.008
Elevated C-reactive protein, n(%)	48 (49)	26 (68.4)	0.041

Discussion

Since it was isolated from the urine of patients with renal tubular dysfunction in 1968 by Berggard and Bearn, β2M has been a subject to several studies [22]. As most of the free β2M in the circulation is excreted by glomerular filtration, it may be used for measuring the GFR [23]. While the main source of serum free β2M is lymphocytes; an increase in the serum levels may be related either to renal dysfunction or to lymphocyte activation in lymphoproliferative or autoimmune diseases in patients with normal renal function [4] [24]. In a study with 100 SLE patients, the serum β2M levels were found significantly higher in SLE patients when compared to the healthy control group (p<0.001), and it was shown that there is a significant correlation between serum β2M levels and SLE activity indices such as anti-dsDNA, complement and hemoglobin levels and the Systemic Lupus Erythematosus Disease Activity index (SLEDAI) [9]. In a study conducted by Aghdashi et al. with 50 SLE patients, the serum β2M levels were found to be significantly higher than healthy controls and were related to SLE disease activity (p<0.001 and p<0.001, respectively) [24]. In a similar study by Zychowska et al. with 69 SLE patients, it was shown that serum β2M levels correlated with SLEDAI, complement 4 levels and anti-dsDNA titers [25]. In a multicentric study carried out by Gottenberg et al. with primary Sjögren’s syndrome patients at 15 centers, it was demonstrated that increased β2M levels were associated with increased EULAR Sjögren’s Syndrome Disease Activity Index (p<0.001) [26]. A study conducted with 192 Sjögren’s syndrome patients, it was shown that the unstimulated whole salivary β2M levels in both primary and secondary Sjögren’s syndrome patients were significantly higher than both the healthy control group and the non-Sjögren sicca symptom group [27].

On the one hand, studies demonstrating increased serum β2M levels in autoimmune diseases and positively correlated with disease activity indices have been popular in recent years. On the other hand, there are a few studies in the literature evaluating the relationship between RA and serum β2M levels which were conducted almost 3 decades ago. For this reason, in this study, we aimed to analyze the serum β2M levels in RA patients and its correlation with disease activity indices. Our study included a total of 137 RA patients. Even though, there was a significant age difference between 3 study groups; as serum β2M levels do not vary according to age or sex as long as GFR is within normal range, the differences among the groups were not assumed to be significant. In similarity to the few previous studies with RA patients, we found significantly higher serum β2M levels in RA patients in comparison to the healthy control group. As far as we know, the first study on RA patients was conducted in 1975 and reported that β2M levels in the synovial fluid specimens collected from ten active RA patients, 11 non-RA inflammatory arthritis and 8 degenerative arthritis patients were significantly higher in RA patients when compared to the other 2 groups (p<0.01 and p<0.001, respectively) [28]. In 1978, Manicourt et al. examined the β2M levels in the plasma and 24-hour urine of 21 RA patients and showed that the plasma β2M levels were at the upper limit of normal in more than 50%, and the urine β2M levels were at the upper limit of normal in the 30% of the patients [29]. In the study carried out in 1980 by Sjöblom et al. with 135 RA patients, the plasma β2M concentration was found to be high in 33% of the patients [30]. A study in 1981 with 20 healthy control and 44 RA patients found significantly increased serum β2M levels in RA patients [3]. In 1989, in a study including 57 active RA patients, the mean β2M levels in both serum and synovial fluids of RA patients were found to be significantly high, but the synovial fluid β2M levels were found to be higher than the serum levels in 76% of the patients [31]. While β2M is expressed at a certain level in most cells, its expression is stimulated especially in the presence of interferon-α (IFN-α) [32]. Increased β2M induces interleukin 6 (IL-6), IL-8 and IL-10 expressions and coordinates the relationship between cytokines and receptors [6] [33] [34]. It is believed that IFN-α may have a role in the pathogenesis of RA. Increased IFN-α levels were shown in the synovial tissues and peripheral circulation of RA patients [35] [36].

In this study, in difference to previous studies, DAS28-ESR, DAS28-CRP, SDAI and CDAI were used to assess RA disease activity. We found a significant positive correlation between the serum β2M levels and these 4 indices. In the subgroup analysis, the RA patients were divided into 2 groups based on their disease activities according to DAS28-ESR. The serum β2M levels in the group with moderate and high disease activity with DAS28-ESR ≥3.2 (n=62) were significantly higher than the group with remission and low disease activity group with DAS28-ESR<3.2 (n=75). The serum ESR and CRP levels were also found to be significantly higher in the DAS28-ESR ≥3.2 group. This result shows that serum β2M levels are related to disease activity. In contrast to previous studies, in our study we found a significant positive correlation between the serum β2M levels and ESR and CRP levels. Manicourt et al found no correlation between β2M and ESR [29]. Sjöblom et al found a weak relationship between β2M levels and other markers of joint inflammation [30]. In the study of Latt et al, no correlation was found between serum and urine β2M levels and ESR and lymphocyte counts [3]. On the other hand, similar to our study, in more recent studies conducted with autoimmune diseases other than RA, positive correlations between serum β2M levels and disease activity indices were found [9] [26]. In a study by Aygündüz et al. with 43 Behçet syndrome patients, it was also shown that the serum β2M levels of the active patients were higher than those of the inactive patients and the healthy control group [4]. This difference could be explained by the largest number of RA patients included in our study and nowadays, laboratory measurements are more sensitive than approximately 30 years ago. Furthermore, in our study, we used RA disease activity indices that are frequently used in recent years and are more sensitive to assess disease activity, thus, we believe that our results are more reliable in reflecting disease activity in comparison to previous studies. In this study, we also found a significant relationship between the β2M levels and SJC, but we could not find the same relationship with TJC. This may be due to TJC being a more subjective finding depending on the patient’s perception of pain, but SJC is more reliable in showing synovial inflammation.

In our study, we also compared serum β2M levels of the RA patients with 102 AS patients. Accordingly, the β2M levels of RA patients were found to be significantly higher than in AS patients. There was no significant difference between serum β2M levels of AS patients and healthy controls. In this study, the disease activity of AS patients were also assessed by BASDAI, BASFI, ASDAS-CRP and ASDAS-ESR, and the correlations between these scores and serum β2M levels were examined. Consequently, no significant correlation was found between the serum β2M levels and BASDAI, BASFI, ASDAS-CRP and ASDAS-ESR. Nevertheless, as found in RA patients, there was a statistically significant correlation between β2M and ESR and CRP in AS patients. The results we found in AS patients were similar to previous studies in the literature. In a study by Wendling et al. with 28 AS patients, the serum β2M levels of the patients were found to be within normal limits, and no relationship was found between β2M levels and other inflammation markers [37]. In a study by Kepekçi et al. with 20 AS patients, the serum β2M levels were also found to be not significantly different than the control group, and its relationship with serum ESR, CRP and fibrinogen levels could not be demonstrated [38]. Beersma et al. found the serum β2M levels in HLA-B27 (+) acute anterior uveitis patients in normal limits and reported that the presence of concomitant AS did not change the result [39].

Our study had some limitations. First of all, this was a cross-sectional study. Prospective studies analyzing the changes in the serum β2M levels of RA patients after treatment will be useful to clarify the relationship between serum β2M levels and RA.

To sum up, in this study it was found that serum β2M levels increase in RA patients and are correlated with disease activity. As measuring β2M is easy, fast and reliable, in patients without underlying renal or lymphoproliferative diseases, serum β2M can be used as a disease activity marker in RA patients.

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