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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 213-219

Clinical significance of elevated antinuclear antibodies in patients with diffuse large B-cell lymphoma: A single center study


1 Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan; Department of Hematology, Jincheng Dayi Hospital, Jincheng, China
2 Department of Hematology, Jincheng People's Hospital, Jincheng, China
3 Department of Hematology, Jincheng Dayi Hospital, Jincheng, China
4 Department of Radiation Oncology, Sichuan Cancer Hospital, Sichuan, Chengdu, China
5 Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China

Date of Web Publication8-Mar-2018

Correspondence Address:
Prof. Hui Sun
Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.183559

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 > Abstract 

Objective: To investigate the potential diagnostic and prognostic values of antinuclear autoantibodies (ANAs) in diffuse large B-cell lymphoma (DLBCL).
Materials and Methods: Eighty-two DLBCL patients and 120 healthy controls were selected from the Department of Hematology, Jincheng Dayi Hospital between 2005 and 2014. We examined the expression of ANA in the sera of the 82 DLBCL patients at different Ann-Arbor stages (15 at Stage I, 22 at Stage II, 27 at Stage III, and 18 at Stage IV). ANA detection was performed by immunofluorescence, and the results were confirmed by Western blotting analysis.
Result: ANAs were more frequently detected in DLBCL patients than in controls (P < 0.001), with 25 (30.5%) DLBCL patients and 9 (7.5%) controls displaying elevated ANA levels. However, the majority of DLBCL patients in which ANA were detected did not develop autoimmune diseases, suggesting that ANA in DLBCL might not be correlated autoimmune diseases. Furthermore, no correlation was observed between the expression of ANA and the clinical stages of DLBCL. However, ANA-positive DLBCL patients had a better survival rate (P < 0.05).
Conclusions: ANA in DLBCL may be a stage-independent prognostic factor rather than an indication for autoimmune diseases and may represent an effective immune response to the tumor.

Keywords: Antinuclear antibodies, diffuse large B-cell lymphoma, indirect immunofluorescence, prognostic values


How to cite this article:
Lang J, Ma K, Guo J, Zhang J, Wang Q, Sun H. Clinical significance of elevated antinuclear antibodies in patients with diffuse large B-cell lymphoma: A single center study. J Can Res Ther 2018;14:213-9

How to cite this URL:
Lang J, Ma K, Guo J, Zhang J, Wang Q, Sun H. Clinical significance of elevated antinuclear antibodies in patients with diffuse large B-cell lymphoma: A single center study. J Can Res Ther [serial online] 2018 [cited 2021 Jun 24];14:213-9. Available from: https://www.cancerjournal.net/text.asp?2018/14/1/213/183559


 > Introduction Top


Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for 30–40% of NHL cases.[1] Its clinical manifestations, morphologies, immune phenotypes, and genetic features are extremely heterogeneous.[2] It is well known that an association exists between the pathogenesis of lymphomas and autoimmune diseases.[3],[4],[5] Autoantibodies are detected at higher frequency in lymphoproliferative diseases; however, neither the precise role of the immune system nor the cause of this is clear. A previous study investigated the presence of antinuclear autoantibodies (ANAs) in a large cohort of patients with DLBCL to assess the frequency, specificity, and prognostic relevance of ANA and reported that DLBCL patients were frequently positive for ANA (56.3%).[5]

ANAs found in malignancy have been regarded as an expression of autoimmunity that may occur sporadically, but the mechanisms by which this autoimmunity develops are unclear.[6],[7],[8] Although ANA in systemic autoimmune diseases has shown considerable disease specificity, ANA in cancer are thought to be characterized by reactivity to generally distributed nuclear antigens.[6],[9] The association between autoimmune disease and NHL is still not fully understood. Some have speculated that ANA represents an important component of the natural autoantibody repertoire and may participate in anti-tumor immunosurveillance.[10] A possible link is the CD5+ B-cell population, which represents 20% of B-cells in adult blood and spleen:[11] These CD5+ B-cells constitute a functionally distinct subset of autoantibody-producing cells that can contribute to the association between B-lymphoproliferative disorders and specific autoimmune diseases.[12] Imai et al.[13],[14] suggested that changes in ANA responses may reflect early carcinogenic events and that, in hepatocellular carcinoma, such changes in ANA levels may reflect an autoimmune response to nuclear antigens that are perturbed in cellular transformation.

In our present study, we investigated a number of ANA in DLBCL patients. The prevalence and clinical significance of ANA and ANA-related autoantibodies were determined in 82 DLBCL patients.


 > Materials and Methods Top


Patients

A total of 82 patients with a confirmed diagnosis of DLBCL based on pathologic review and 120 age-matched controls were recruited from Jincheng Dayi Hospital between January 2005 and June 2014. These patients had either newly diagnosed disease or active disease being treated by chemotherapy. As the appearance of autoantibodies may be found after treatment of DLBCL, samples were collected at the time of diagnosis of DLBCL before patients received any therapy. When lymphoma was diagnosed, the presence autoimmune diseases were recorded. None of the patients exhibited complete remission of the lymphoma at the time of blood sampling. Patients who were positive for autoantibodies were regularly followed up by an experienced hematologist until June 2014 to verify the development of symptoms indicative of autoimmune disorders. Specific questions about the presence of signs or symptoms related to autoimmune diseases were asked, and any developments of arthritis, mucosal dryness, joint pain or swelling, persistent rashes, morning stiffness, myalgia, and diarrhea were recorded. These patients were evaluated according to age, sex, stage, B symptoms, extranodal involvement, and lactate dehydrogenase level.

Of the 82 DLBCL patients, 51 were male and 31 were female, with a median age of 43 years (range, 20–72 years) for males and 38 years for females (range, 18–75 years). One hundred twenty sera samples (70 from males and 50 from females, with a median patient age of 45 years [range, 22–70 years]) were selected from individuals, who were undergoing examination in different Clinical Departments of the same hospital and had no evidence of malignancy or known autoimmune diseases. The diagnoses of autoimmune diseases were based on traditional clinical criteria and published guidelines. Outcomes and the effects of autoantibodies on the remission rate were not evaluated in this study. All sera samples were stored at −80°C before use.

All patients were characterized according to the Ann-Arbor system by clinical examination.[15] Performance status was assigned according to the Eastern Cooperative Oncology Group Scale,[16] and the International Prognostic Index was calculated as described previously.[17] All patients were treated by chemotherapy according to patients' clinical characteristics and histopathology. All participants provided informed consent in accordance with the Declaration of Helsinki. This study was approved by the Ethics Committee of Jincheng Dayi Hospital.

Indirect immunofluorescence analysis

We used a commercially available kit (EUROIMMUN, Germany) for the detection of ANA according to the manufacturer's instructions. IgG ANA-screening in Hep-2 cells (EUROIMMUN, Germany) was performed by indirect immunofluorescence essentially as described previously.[18] Hep-2 cells originate from a human larynx carcinoma that was grown in rats [19] and was routinely used to detect and classify ANA that was characteristic of various autoimmune systemic connective tissue diseases.[20]

EUROLINE analysis

Western blotting was performed using the EUROLINE ANA profile 3 IgG kit (EUROIMMUN AG, Lübeck, Germany). The film strip was removed and placed in the incubation tank. Sample buffer (1.5 mL) was added and incubated in a shaker (EUROIMMUN AG, Lübeck, Germany) at room temperature for 5 min, before the absorption of liquid into the tank. Diluted serum sample (1.5 mL) was then added into the incubation vessel and agitated at room temperature (18–25°C) for 30 min incubation. Following incubation, the liquid was absorbed into the tank, and the film strip was washed three times in a shaker with 1.5 mL washing buffer for 5 min/time. A total of 1.5 mL diluted enzyme conjugate (alkaline phosphatase-labeled anti-human IgG) was added into the incubation tank and then agitated in the shaker at room temperature for 30 min. The liquid was subsequently absorbed into the tank, and the film strip was washed three times before 1.5 mL substrate solution was added. After another incubation at room temperature for 10 min, the film strip was washed three times with distilled water. The film strip was then rotated in the result detecting template (ANAs Profile 3; EUROIMMUN AG) for analysis following air-drying. ANA-related autoantibodies against PM-Scl, dsDNA, ssDNA, CENP-B (ACA), nucleosome, Sm, P0, histones, U1-SnRNP/Sm, SS-A (Ro-60), SS-A (Ro-52), SS-B (La), Scl-70, and Jo-1 were detected as autoimmune markers via EUROLINE assays.

Statistical analysis

Clinical characteristics between the groups were compared using independent t-tests for continuous variables and Pearson's Chi-square tests for categorical variables. Overall survival (OS) was calculated as the time from the date of first pathological diagnosis until death from any cause. OS and progression-free survival were estimated using the Kaplan–Meier method, and the log-rank test was used to assess the survival differences between groups.

Cox regression analysis was used to investigate whether ANA levels can serve as a stage-independent prognostic factor. The Cox proportional hazard model was used for multivariate analysis to correct for the effect of the stage and assess the independent effects of prognostic variables on outcomes. A P < 0.05 was considered statistically significant. Data were analyzed using SPSS software (version 17.0 for Windows, SPSS Inc., Chicago, IL, USA).


 > Results Top


Sera samples from 25 patients (8 females and 17 males) out of the 82 patients with DLBCL (30.50%) and 9 individuals (5 females and 4 males) out of the 120 participants in the control group (7.50%) displayed ANA with a titer ≥1:100 [Table 1]. The distributions of patients' characteristics and clinical stage of DLBCL are shown in [Table 2]. Ann-Arbor clinical staging revealed that 18 patients (22%) had Stage IV disease, 27 (33%) had Stage III disease, 22 (27%) had Stage II disease, and 15 (18%) had Stage I disease in the DLBCL Group [Table 2]. The ANA titer varied from 1:100 to 1:320 in the sera of control individuals and from 1:100 to 1:10,000 in sera of the DLBCL patients [Table 3]. This difference between the patient and control groups was found to be significant (P< 0.0001). The speckled pattern [Figure 1] was found to be the most frequent immunofluorescent pattern with a significant difference between DLBCL samples and those from the control group (P = 0.002).
Table 1: Prevalence and immunofluorescence patterns of antinuclear autoantibodies in diffuse large B-cell lymphoma patients and in the control group

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Table 2: Distribution of stages of diffuse large B-cell lymphoma

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Table 3: Antinuclear autoantibodies titers in the antinuclear autoantibodies -positive diffuse large B-cell lymphoma (25/82) and control (9/120) groups showing homogeneous, speckled, and nucleolar patterns

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Figure 1: Indirect immunofluorescence pattern of antinuclear autoantibodies positivity observed for diffuse large B-cell lymphoma patients on HEp2 cells (×40)

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The elevated ANA levels in the 25 ANA-positive DLBCL patients varied from 1:100 to 1:10,000, and the levels of ANA did not differ significantly among the different stages of DLBCL (P = 0.978). The male:female ratio was 17/8 among ANA-positive DLBCL patients, with no significant difference found between male and female patients in terms of ANA positivity (P = 0.094).

Identification of ANA showed that 6 out of 14 patients (7.3%; 1 male and 5 females) with a speckled ANA pattern were positive for anti-SS-A (Ro-60), anti-SS-A (R0-52), and anti-SS-B (La) autoantibodies [Figure 2]. Four patients (4.9%; 2 males and 1 females) were positive for anti-PM-Scl [Figure 3], and 4 patients (4.9%; 3 males and 1 female) were positive for anti CENP-B (ACA) [Figure 4]. None of these DLBCL patients were positive for anti-ssDNA, anti-Sm, anti-P0, anti-histones, or anti Jo-1 antibody. No participants from the control group were positive for anti-dsDNA, anti-SS-A (Ro-60), anti-SS-A (Ro-52), or anti-SS-B (La) autoantibodies.
Figure 2: EUROLINE images of target antigens of antinuclear autoantibodies. Positive staining for anti-SS-A (Ro-60), anti-SS-A (Ro-52), and anti-SS-B (La) was observed for antinuclear autoantibody-positive diffuse large B-cell lymphoma patients

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Figure 3: EUROLINE images of target antigens of antinuclear autoantibodies. Positive staining for PM-Scl was observed for antinuclear autoantibody-positive diffuse large B-cell lymphoma patients

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Figure 4: EUROLINE images target antigens of antinuclear autoantibodies. Positive staining for CENP-B (ACA) was observed for antinuclear autoantibody-positive diffuse large B-cell lymphoma patients

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The clinical and laboratory data for these patients were analyzed to identify any associations between ANA positivity and signs of autoimmune disease. One DLBCL patient had psoriasis when admitted to the hospital. Except for this patient, none of the DLBCL patients had an autoimmune disease before diagnosis with lymphoma. By the end of the follow-up period, 8 (9.76%) patients had developed autoimmune diseases: 4 had Sjogren's syndrome, 1 had rheumatoid arthritis, 1 had arthralgia and myalgia, 1 had arthralgia, and 1 had Raynaud's syndrome [Table 4]. No sign of any autoimmune disease was found in the other 17 ANA-positive patients. Two specific serological abnormalities, SS-A and SS-B, were found in patients with DLBCL and SS. Given the relatively low frequency of clinical and biological symptoms of autoimmunity in the general population, these findings suggest that ANA detection was more likely to be associated with those clinical or biological features although some patients with high antibody titers did not present any symptoms.
Table 4: Clinical and/or biological signs of autoimmunity

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To evaluate whether patients with ANA had a different disease outcome compared with those without these biological markers, time to progression and OS were assessed in these patients. The outcome was found to be significantly different between these two populations [P = 0.003, [Figure 5]. Cox regression analysis showed that ANA was a stage-independent prognostic factor [P = 0.032, [Table 5].
Figure 5: Survival curves for antinuclear autoantibody-positive and autoantibody-negative diffuse large B-cell lymphoma patients shown in a Kaplan–Meier plot (P = 0.003)

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Table 5: Cox regression analysis of stage, antinuclear autoantibodies positivity, age, and sex for overall survival

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 > Discussion Top


Many studies have reported that patients suffering from NHL can display clinical or biological features of autoimmunity, especially autoantibodies such as ANA.[21],[22] However, these initial findings were observed mostly in patients after treatment and, therefore, may rather represent the effect of NHL-specific treatment, which is known to induce the production of different autoantibodies.[23],[24] Guyomard et al.[5] analyzed the ANA positivity at the time of diagnosis of DLBCL and before any specific treatment. Their analysis showed that sera samples from 66 out of 347 (19%) patients with NHL displayed an ANA titer of 1:160. A significantly lower frequency (5.6%; P < 0.001) was observed in sera from the control group. To verify this point further, in our study, we analyzed the presence of ANA at the time of diagnosis of DLBCL and before any specific treatment. Our results were consistent with those of the study by Guyomard et al.; however, an even higher rate of ANA positivity (30.5%) was found in our DLBCL patient cohort. Previous studies have indicated the percentage of ANA positivity among NHL patients to be as high as 32%, but their analyses were performed during or after lymphoma treatment.[21],[22] In our study, there was a small difference in the mean age between the patient and control groups; however, this difference is unlikely to have any effect on the results. Although autoantibodies are more prevalent in the elderly population,[6] they are usually of low titer, unlike those we reported here.

Our study showed that the ANA titer distribution in the DLBCL group was wider compared with control group. It indicated that ANA is a common autoimmune phenomenon in DLBCL. However, the association between ANA and NHL is still not fully understood. Some have speculated that ANA represents an important component of the natural aAbs repertoire and might participate in an antitumor immunosurveillance.[10] A possible link is the CD5+ B-cell population.[11] Accumulated evidence indicates that the autoreactive B repertoire frequently undergoes malignant transformation.[25] Moreover, Fas mutations can also be implicated in the association between lymphoma and autoimmunity. These mutations have been identified in 60% of mucosa-associated lymphoid tissue lymphomas, 21% of DLBCLs, 6% of follicle center cell lymphomas, and 50% of anaplastic large-cell lymphoma.[26]

Another bias that can increase the frequency of ANA positivity is the choice of the cutoff level for sera positivity. A previous study showed that healthy individuals generally are negative for ANA but can be regarded as positive depending on the cutoff level.[27] We used a cross-matched age population as the healthy control group in the present study to eliminate this potential bias.

Considering the association between the diseases, autoimmune diseases not only can develop over the course of the lymphoproliferative disorder but also can precede the diagnosis of lymphoma.[28] Well-defined and incomplete autoimmune syndromes have been described in NHL including thyroiditis, autoimmune hemolytic anemia, rheumatoid arthritis, Sjogren's syndrome, urticaria phenomena, cold agglutinin disease, nephrotic syndrome, vasculitis, systemic lupus erythematosus (SLE), and scleroderma.[28],[29],[30],[31],[32],[33] Thus, the correlation between the presence of ANA and clinical manifestations of autoimmune disorders was evaluated in this study. More than 25% of ANA-positive patients displayed some autoimmune clinical symptoms or a well-defined autoimmune disease, i.e., Sjogren's syndrome (4 cases), Raynaud's syndrome (1 case), Arthralgia, myalgia (2 cases), cutaneous nodosities (1 case), and rheumatoid arthritis (1 case). The risk of occurrence of B-cell NHL in Sjogren's syndrome has been estimated to be almost 50 times greater than that in the age-matched control individuals [34],[35] with a high incidence of marginal zone lymphoma.[36],[37] We have not yet observed any occurrence of SLE reported in NHL although the overall cancer incidence is reported to be significantly increased by 30% in SLE patients compared with that of the general population.[36],[38] In the present study, the majority of the patients positive for ANA or cytoplasmic autoantibodies did not display autoimmune clinical symptoms, demonstrating the lack of a strict correlation between the presence of such ANA and autoimmune symptoms or disease.

Previously, it was demonstrated that the presence of autoantibodies in the serum of patients with breast cancer was associated with a higher risk of recurrence or metastases in a follow-up of 2 years.[39] Other studies suggest that the presence of ANA or dsDNA autoantibodies appears to correlate with a better clinical outcome in patients with small-cell lung [40] and colorectal cancers;[41] however, no prognostic association was found in NHL patients in a previous study.[5],[22] Here, we also evaluated the relationship between the frequency of ANA in DLBCL and their relation to outcome. In our study, the results revealed that ANA-positive DLBCL patients had significantly better survival outcomes than ANA-negative DLBCL patients. In addition, our results showed that concordant ANA-positivity had a negative effect on OS, independent of the disease stage. Our observation regarding the relation between some autoantibodies and OS may be related to the expression of particular antigens at different stages of tumor progression.

Some autoantibodies have already been used as an indicator for cancers such as autoantibodies to p62, Koc, and CENP-F in patients with hepatocarcinoma.[42],[43] Other studies have shown that early detection of autoantibodies to some neuronal proteins (Hu, Ri, and Yo) in patients with paraneoplastic neurological syndromes can aid the diagnosis of small cell lung, breast, and ovarian carcinomas.[44] It would be of great interest to identify the target antigens of ANA that may be used as markers for some NHL subgroups.


 > Conclusions Top


Our study has demonstrated a significant incidence of ANA positivity in DLBCL patients before any treatment. However, the majority of ANA-positive DLBCL patients did not display signs of autoimmune diseases, suggesting that a correlation between ANA positivity and autoimmune disease among DLBCL patients is unlikely. Instead, ANA positivity in DLBCL patients was associated with better survival outcomes. However, longer term regular follow-up is needed to further validate the findings of this study.

Acknowledgments

This revised manuscript has been edited and proofread by Medjaden Bioscience Limited. The authors gratefully thank Medjaden Bioscience Limited for excellent assistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Antoine JC, Honnorat J. Anti-neuronal antibodies and central nervous system diseases: Contribution to diagnosis and pathophysiology. Rev Neurol (Paris) 2000;156:23-33.  Back to cited text no. 44
    


    Figures

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