|Ahead of print publication
Correlation of B-cell-activating factor levels and diseases activity in systemic lupus erythematosus patients
Ria Yolanda Vitri1, Rachmat Gunadi Wachjudi2, Nadia Gita Ghassani3, Laniyati Hamijoyo4
1 Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
2 Department of Internal Medicine, Division of Rheumatology, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
3 Lupus Study Group, Immunology Study Center, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
4 Department of Internal Medicine, Division of Rheumatology, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital; Lupus Study Group, Immunology Study Center, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
|Date of Submission||07-May-2020|
|Date of Acceptance||13-Jul-2020|
Department of Internal Medicine, Division of Rheumatology, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung; Lupus Study Group, Immunology Study Center, Faculty of Medicine, Universitas Padjadjaran, Jalan Professor Eyckman No. 38, Bandung, West Java 40161
Source of Support: None, Conflict of Interest: None
Background: B-cell hyperactivity is believed to have a central role in the pathogenesis of systemic lupus erythematosus (SLE). B-cell-activating factor (BAFF) is a cytokine that plays a role in accelerating maturation, differentiation, and survival of B-cells. The purpose of this study is to determine whether there is a significant association between the serum BAFF levels and disease activity in SLE patients. Subjects and Methods: This study uses bivariate analysis with a cross-sectional design. The statistical analysis test used is Pearson's and Spearman's correlation coefficient test, as well as Mann–Whitney test. Participants were 44 SLE patients with active disease (SLEDAI 2K >2) in the rheumatology clinic and in-patient wards of Hasan Sadikin General Hospital, Department of Internal Medicine, Bandung, during the period of December 2016–March 2017. Results: Forty-four participants of the study were women with a mean age of 28 ± 8 years. Renal (93.2%) and mucocutaneous (93.2%) involvements were the most common manifestations. Median of disease activity based on SLEDAI-2K score was 8 (4–23). Median serum BAFF level was 1.218 ng/ml (0.476–10.835). There was a weak positive correlation between serum BAFF levels and SLEDAI-2K (r = 0.327, P = 0.015). There was also a significant correlation with weak relation found between serum BAFF levels and anti-dsDNA and complement C3 levels. Conclusion: There is a significant correlation between the serum levels of BAFF and SLE disease activity. However, the strength of the relationship is weak. Therefore, disease activity in lupus can be influenced by other factors.
Keywords: B-cell-activating factor, disease activity, Indonesia, systemic lupus erythematosus, Systemic Lupus Erythematosus Disease Activity Index 2000
|How to cite this URL:|
Vitri RY, Wachjudi RG, Ghassani NG, Hamijoyo L. Correlation of B-cell-activating factor levels and diseases activity in systemic lupus erythematosus patients. Indian J Rheumatol [Epub ahead of print] [cited 2021 Jan 21]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=297397
| Introduction|| |
Systemic lupus erythematosus (SLE) is an autoimmune disease with very diverse clinical manifestations and includes multiple organs. This chronic disease has a period of exacerbation and remission that is difficult to predict and control. Formation of autoantibodies that primarily attack the nuclear antigens is the hallmark of SLE. Autoantibodies will initiate inflammatory response in multiple organs that results in clinical manifestations of the disease., Interaction between genetic variation, environmental, metabolic, and hormonal factors activates different inflammatory pathways and trigger diverse clinical manifestations.,
Several mechanisms of immune system dysregulation play a role in the pathogenesis of SLE, encompassing both innate and adaptive immunity. This dysregulation includes B-cell hyperactivity, T-cell hyperactivity, phagocytic functional abnormalities, and hypocomplementemia due to overuse and reduce production of C1q, C2, C3, C4, and CH50. Various studies have been conducted to find genetic, epigenetic, and biochemical factors (cytokines and chemokines) involved in the immunopathogenesis of SLE. The role of B-cells becomes very important and central in the pathophysiology of SLE.
In SLE patients, the number of levels and activity of transitional B-cells, plasma cells, and plasmablasts is found to be increased. Several years ago, researchers discovered B-cell activating factor (BAFF) or B-lymphocyte stimulator, a factor associated with B-cell hyperactivity. BAFF is a superfamily of tumor necrosis factor that plays a role in maturation, differentiation, and survival of B-cells. In addition to increasing the population of B-cells, BAFF also induces the turnover of immunoglobulin to become more pathogenic. In the early phase of inflammation, BAFF has an important role in recruiting other immune cells that results in a more severe inflammation occurs in the target organ of SLE. Moreover, all cytokines produced by immune cells will also enhance the BAFF itself, which results in an overexpression of BAFF.
There is an increase in serum BAFF levels by a varying percentage in SLE patients. Genetic factors (polymorphism), race, age, cigarette smoking, and anti-dsDNA levels are thought to play a role in this variation. Since the role of BAFF in the pathogenesis of SLE is widely known, it is thought that BAFF has an important role in the initial pathogenesis of SLE as well as in SLE flares. Several studies have proven that higher BAFF levels are found in active SLE patients, with their correlation to disease activity remain controversial.,
Disease activity is defined as a clinical or laboratory manifestation, that is reversible and it reflects the immunological or inflammatory states of a particular organ at one time. The fluctuating activity of SLE requires the monitoring of clinical parameters that are objective, valid, and sensitive toward changes. Although there is no gold standard yet for measuring SLE disease activity, there are several methods known in determining the disease activity, both globally, which represents the overall inflammation inside the body, and specifically, toward certain organs involved. One of the known tools to measure SLE disease activity is the SLE Disease Activity Index 2000 (SLEDAI-2K). There is no single biomarker that found can accurately represent SLE disease activity.
Studies on BAFF and disease activity have already been conducted in other countries. However, there are no studies on the role of BAFF in SLE disease activity in Indonesia. Thus, this study aims to determine the correlation between serum BAFF levels and SLE disease activity based on SLEDAI-2K scores in SLE patients.
| Subjects and Methods|| |
This is an analytical, descriptive study with a cross-sectional design that obtains its primary data from SLE patients in Hasan Sadikin General Hospital Bandung. The participants of this study were SLE patients diagnosed based on the American College of Rheumatology 1997 criteria or Systemic Lupus International Collaborating Clinics 2012 criteria, who visited rheumatology outpatient clinic or have been hospitalized in Hasan Sadikin General Hospital Bandung from December 2016 until March 2017. The inclusion criteria of this study were (1) all SLE patients who were at least 14 years old, (2) agreed to participate in this study, and (3) had SLEDAI-2K score > 2. SLEDAI-2K score more than 2 reflected the disease is active.
This study excluded SLE patients (1) who were pregnant, (2) had overlap syndromes, which is lupus and other connective tissue diseases such as scleroderma or rheumatoid arthritis (3) had comorbid diseases such as human immunodeficiency virus and hepatitis C virus infection, hepatic cirrhosis, chronic lymphocytic leukemia, and Hodgkin and non-Hodgkin lymphoma, (4) and active smoker. These exclusion criteria were based on previous studies that reported an elevated levels of BAFF on these diseases and pregnancy that could lead to bias in this study. People who smoke will also have higher serum BAFF levels due to the particles from cigarette smoke can stimulate respiratory tract epithelium to express BAFF and inducing inflammation.
This study collected primary data consisting of serum BAFF from the participants and their disease activity, as measured by SLEDAI-2K. Written informed consent had been obtained from all participants. After the SLEDAI-2K descriptors were assessed, three milliliters of blood from participants were drawn intravenously and then placed into a tube without anticoagulant for 30 min. Blood then centrifuged with speed of 3000 rpm for 15 min. Serum that was formed then stored in microtube below −20°C temperature until all serum were collected. From the serum, BAFF level then measured simultaneously with indirect ELISA method.
Baseline characteristics of SLE patients, such as age, duration of SLE, organ involvement, C3, and anti-dsDNA levels were also collected from Hasan Sadikin Lupus Registry done in Hasan Sadikin Hospital. Statistical analysis used in this study was Pearson correlation test, if the data were normally distributed, and Spearman, if it was not normally distributed. The Mann-Whitney test was also used for the comparison of median BAFF between the types of organ manifestations. This study was approved by Hasan Sadikin General Hospital Ethics and Research Committee.
| Results|| |
Forty-four participants were enrolled in this study. All of the participants were female and had a mean age of 28 years, while the median duration of SLE was 30 months with a minimum value of 1 month and a maximum of 153 months. Most of the study participants (77.3%) were patients who visited rheumatology outpatient clinic regularly. The remaining 22% were SLE patients who were being hospitalized due to severe flares or undergoing cyclophosphamide chemotherapy.
Most participants (93.2%) had renal involvement. Median anti-dsDNA level was 289.5 IU/ml. Nineteen patients (43%) had anti-dsDNA of more than 300 IU/ml. C3 levels were normally distribution with mean value of 90 mg/dl. Disease activity based on the SLEDAI-2K score had a median of 8. Thirty-one participants (70.5%) had a SLEDAI-2K score of ≥ 8. Median BAFF level was 1.218 ng/mL [Table 1].
|Table 1: Baseline characteristics of systemic lupus erythematosus patients|
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There was a positive correlation between serum BAFF and SLEDAI-2K (r = 0.327, P = 0.015) [Table 2]. This showed that the higher BAFF levels correspond to the higher SLEDAI-2K score. The determinant coefficient (R2) was 0.107, which showed that the impact of serum BAFF on SLEDAI-2K score was only 10.7% [Table 2]. There was also a negative correlation between serum BAFF and C3 (r = −0.361) and a positive correlation with anti-dsDNA (r = 0.259). However, there was no significant correlation between BAFF and type of organ manifestation, as shown in [Table 3].
|Table 2: Correlation between serum B-cell activating factor levels with Systemic Lupus Erythematosus Disease Activity Index 2000, C3, and anti ds-DNA|
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|Table 3: Comparison of B-cell activating factor between type of organ manifestations|
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| Discussion|| |
This study showed that there is a correlation between BAFF levels and disease activity. It is coherent with a lot of studies that suggesting an increase of BAFF levels in active SLE [Table 4].,,, A study by Petri et al. using the multivariate analysis reported that elevated baseline serum BAFF concentration (≥2 ng/mL) was predictive of moderate-to-severe SLE flares in patients receiving the standard therapy such as prednisone with hydroxychloroquine or immunosuppressive drugs. However, in our study, we only measured BAFF and SLEDAI-2K in a single period of time; hence, this study cannot conclude BAFF level as a predictor of SLE flares. Another study by Ju et al. in 2006 also showed a significant difference in BAFF levels between active and inactive SLE groups as the results. In a study conducted on rats, BAFF inhibition can slow the deterioration of kidney function and reduce mortality, which correlates with more severe disease activity.,,
Bivariate analysis of serum BAFF levels in disease activity based on SLEDAI 2K scores in this study showed significant correlation with weak strength (r = 0.327; P = 0.015). These results are in line with other studies in different countries. However, a study by Mercado in 2015 and Ju et al. in 2006 showed a greater correlation (r = 0.45, and r = 0.522, respectively) between serum BAFF and disease activity., This might be due to the fact that all of the participants in our study had previously received treatments, which obviously would make their disease activity more controlled than previous studies that only include naive participants who had not undergone any kind of treatment for SLE. Besides that, median BAFF levels in our study were just above the mildly elevated range, hence would affect the accuracy of correlation between BAFF levels and disease activity.
On the other hand, Zollars et al. in 2016, through a study in 275 SLE patients, stated that BAFF gene expression had a stronger association with disease activity than serum BAFF levels. SLE patients who have higher BAFF gene expression were at a greater risk of proteinuria (20%) than those with low BAFF gene expression (6%). This is might be due to the influence of genomic variations that regulate the BAFF receptors, production of BAFF by other cells/tissues outside the white blood cells, and the effects of these cytokines along with protein in urine from patients with renal involvement that will decrease BAFF levels in serum. Then, findings in this study are based on the measurement of BAFF levels in plasma. However, lupus nephritis involvement, which contributes to more severe disease activity, may increase BAFF excretion in the urine through renal loss, thereby resulting in lower plasma BAFF levels. Future analyses of urine BAFF protein and local production of BAFF (e.g., in lymphatic tissues and joints) may prove to be highly informative.
Multivariate analyses in observational studies have shown that the use of immunosuppressive therapy is positively associated with disease activity and with BAFF level at the current and previous visits. One of the limitations in this study was that most of the participants in this study were patients from outpatient clinic with stable disease activity. All of the participants in this study also had received previous treatment with steroids, immunosuppressants or cytostatic agents, such as azathioprine, methotrexate, cyclosporine, chloroquine, and cyclophosphamide, and they also had a median duration of disease of 30 months. Therefore, these factors might affect the results of the analysis because treatment such as immunosuppressive drugs would lower the disease activity. The lack of uniformity in ELISA tools used in BAFF measurements in different countries is also a factor that give rise to the variation of the results of the study.
Another limitation of this study was the cross-sectional design used in this study which can only assess the effect of BAFF toward SLEDAI in a single period of time. A subsequent study with a prospective cohort method for the following patients visits are needed to determine the role of BAFF as an early marker of SLE flares as well as cutoff of the BAFF levels for predicting exacerbation of SLE. However, despite the limitation of the study, this study remained as one of the first studies to determine the correlation of BAFF and SLE disease activity in Indonesia.
| Conclusion|| |
This study showed a positive correlation with statistically significant, but weak strength between the serum levels of BAFF and disease activity in SLE patients, which is depicted by SLEDAI-2K score. Moreover, the evident role of increased BAFF in SLE disease activity indicates that an anti-BAFF therapeutic approach might prove beneficial in controlling disease activity. However, it still requires a lot of research in future.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Hahn BH. The pathogenesis of SLE. In: Wallace DJ, Hahn BH, editors. Dubois' Lupus Erythematosus. 8th
ed.. Los Angeles: Elsevier; 2013.
Liu Z, Davidson A. Taming lupus-a new understanding of pathogenesis is leading to clinical advances. Nat Med 2012;18:871-82.
Nyoman SI. Immunopathogenesis of Systemic Lupus Erythematosus. 6th
ed.. Jakarta: Pusat Penerbitan Ilmu Penyakit Dalam; 2014. p. 3331-50.
Azaola AH, Guerrero JS. Overview and clinical presentation. In: Wallace DJ, Hahn BH, editors. Dubois' Lupus Erythematosus. 8th
ed.. Philadelphia: Elsevier; 2013.
Liu CC, Kao AH, Manzi S, Ahearn JM. Biomarkers in systemic lupus erythematosus: Challenges and prospects for the future. Ther Adv Musculoskelet Dis 2013;5:210-33.
Cancro MP, D'Cruz DP, Khamashta MA. The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. J Clin Invest 2009;119:1066-73.
Davidson A. The rationale for BAFF inhibition in systemic lupus erythematosus. Curr Rheumatol Rep 2012;14:295-302.
Vincent FB, Morand EF, Schneider P, Mackay F. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol 2014;10:365-73.
Vincent FB, Morand EF, Mackay F. BAFF and innate immunity: New therapeutic targets for systemic lupus erythematosus. Immunol Cell Biol 2012;90:293-303.
Petri M, Stohl W, Chatham W, McCune WJ, Chevrier M, Ryel J, et al
. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum 2008;58:2453-9.
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725.
Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al
. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677-86.
Yee CS, Farewell VT, Isenberg DA, Griffiths B, Teh LS, Bruce IN, et al
. The use of systemic lupus erythematosus disease activity index-2000 to define active disease and minimal clinically meaningful change based on data from a large cohort of systemic lupus erythematosus patients. Rheumatology (Oxford) 2011;50:982-8.
Lied GA, Berstad A. Functional and clinical aspects of the B-cell-activating factor (BAFF): A narrative review. Scand J Immunol 2011;73:1-7.
Eilertsen GØ, Van Ghelue M, Strand H, Nossent JC. Increased levels of BAFF in patients with systemic lupus erythematosus are associated with acute-phase reactants, independent of BAFF genetics: A case-control study. Rheumatology (Oxford) 2011;50:2197-205.
Hamijoyo L, Candrianita S, Rahmadi AR, Dewi S, Darmawan G, Suryajaya BS, et al
. The clinical characteristics of systemic lupus erythematosus patients in Indonesia: A cohort registry from an Indonesia-based tertiary referral hospital. Lupus 2019;28:1604-9.
Petri MA, van Vollenhoven RF, Buyon J, Levy RA, Navarra SV, Cervera R, et al
. Baseline predictors of systemic lupus erythematosus flares: Data from the combined placebo groups in the phase III belimumab trials. Arthritis Rheum 2013;65:2143-53.
Ju S, Zhang D, Wang Y, Ni H, Kong X, Zhong R. Correlation of the expression levels of BLyS and its receptors mRNA in patients with systemic lupus erythematosus. Clin Biochem 2006;39:1131-7.
Mercado U, Díaz-Molina R. B lymphocyte stimulator (BLyS/BAFF) level in sera of patients with lupus. Rev Med Inst Mex Seguro Soc 2016;54:334-7.
Fawzy SM, Gheita TA, El-Nabarawy E, El-Demellawy HH, Shaker OG. Serum BAFF level and its correlations with various disease parameters in patients with systemic sclerosis and systemic lupus erythematosus. Egypt Rheumatol 2011;33:45-51.
Zollars E, Bienkowska J, Czerkowicz J, Allaire N, Ranger AM, Magder L, et al
. BAFF (B cell activating factor) transcript level in peripheral blood of patients with SLE is associated with same-day disease activity as well as global activity over the next year. Lupus Sci Med 2015;2:e000063.
[Table 1], [Table 2], [Table 3], [Table 4]