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ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 110-115

Significance of human leukocyte antigen-B27 expression in cases of reactive arthritis: A study in rural central India


1 Department of Pathology, North Eastern Indira Gandhi Institute of Health and Medical Sciences, Shillong, Meghalaya, India
2 Department of Pathology, Mahatma Gandhi Institute of Medical Sciences, Wardha, Maharashtra, India

Date of Submission29-May-2021
Date of Decision09-Jul-2021
Date of Acceptance11-Jul-2021
Date of Web Publication16-Aug-2021

Correspondence Address:
Anupama Gupta
Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjhs.sjhs_79_21

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  Abstract 


Background: Reactive arthritis (RA), apart from presenting as an immune reaction to certain microorganisms, had also shown to have a genetic predisposition. Human leukocyte antigen (HLA-B27) is an allele of the HLA Class I molecules and its positivity in a person is shown to be a strong predictor of RA. The present study was aimed to study the significance of HLA-B27 positivity in clinical presentation and progress of RA in rural central India. Materials and Methods: One hundred rheumatoid arthritis factor seronegative patients of symptomatic RA were enrolled in the study. HLA-B27 was detected by flow cytometry method and patients were divided into two groups, each of 50 depending on HLA-B27 positivity and negativity as case and control groups. The patients were contacted on their follow-up visits and the clinical information and progress of the disease was assessed and correlated with HLA-B27 status. Results: About 74% in study group and 62% in control groups were males in RA (P = 0.001 and 0.0007, respectively). Study cases with HLA-B27 positivity showed many significant differences in their clinical presentation and disease severity and progression over the control cases (HLA-B27 negative). The mean duration of symptoms in the study group was 22.7 ± 31.26 and 12.98 ± 6.94 in control group. Severity of arthritic pain was more in study group as compared to control group (P = 0.0007). Study cases showed more axial skeletal involvement (P = 0.0002), enthesitis (P = 0.0001), and sacroiliac joint involvement (P = 0.0005). Clinical evaluation of back pain with different clinical tests in study cases showed more morning spinal stiffness (P = 0.0001), low Schober index (P = 0.001), higher lateral flexion (P = 0.0001), and lower chest expansion (P = 0.0001). The severity of disease in follow-up period increased significantly in 92% of patients in the study group despite initiation of clinical management of arthritis, while decreased in 60% of patients in the control group (P = 0.0001). Conclusion: HLA-B27-associated RA presents with significantly more severe primary disease and a rapid course of disease. Thus, HLA-B27 association should be done in all patients of RS and positive patients must be followed more rigorously to prevent many possible complications. To the best of our knowledge, this is the first study in central India to report the importance of HLA-B27 in patients of RA with regard to its management and prognosis.

Keywords: Ankylosing spondylitis, follow-up, human leukocyte antigen-B27, reactive arthritis


How to cite this article:
Shougrakpam J, Deshmukh AV, Gupta A, Gangane NM. Significance of human leukocyte antigen-B27 expression in cases of reactive arthritis: A study in rural central India. Saudi J Health Sci 2021;10:110-5

How to cite this URL:
Shougrakpam J, Deshmukh AV, Gupta A, Gangane NM. Significance of human leukocyte antigen-B27 expression in cases of reactive arthritis: A study in rural central India. Saudi J Health Sci [serial online] 2021 [cited 2021 Dec 8];10:110-5. Available from: https://www.saudijhealthsci.org/text.asp?2021/10/2/110/323884




  Introduction Top


Human leukocyte antigen B27, i.e. HLA-B27, is a serologic specificity that encompasses 25 glycoproteins (HLA-B2701 to HLA-B2725) that are also called subtypes of HLA-B27.[1] HLA-B27 is an allele of the HLA Class I molecules. One of the basic functions of these HLA/major histocompatibility complex (MHC) Class I molecules is to present endogenous peptides derived from intracellular proteins to the αβ T-cell receptor on CD8+ cytotoxic T-lymphocytes. In infected cells, viral peptides are bound by Class I MHC molecules and are presented to the T-cell receptor on cytotoxic T-lymphocytes and the infected cell is lysed.[2]

Currently, reactive arthritis (RA) is defined as immune-mediated synovitis that combines four syndromes: (a) peripheral arthritis syndrome, (b) enthesopathic syndrome (c) pelviaxial syndrome, and (d) extramuscular skeletal syndrome.[3] It results from slow bacterial infections and showing intra-articular persistence of viable nonculturable bacteria and/or immunogenic bacterial antigens synthesized by metabolically active bacteria residing in the joint and/or elsewhere in the body.[3] However, apart from possible association with immune reaction to certain microorganisms, RA is shown to have a genetic predisposition also. Many studies showed that HLA-B27 positivity in a person is a strong predictor of RA.[3] The association of HLA-B27 and RA is illustrated by the fact that the prevalence of disease in HLA-B27-positive individuals is five times greater than in the general population.[4] Moreover, in HLA-B27-positive relatives of patients with RA, the prevalence is another ten times greater.[3]

One of the nationwide epidemiological investigations conducted in China showed that around 78.4% of ankylosing spondylitis (AS) patients were HLA-B27 positive; however, the exact role of HLA-B27 in AS is still unknown.[5] Indian population is known for a range of genetic diversity and the association of HLA-B27 with spondyloarthritis patients is found to be 18%–94%.[6] It was found that the presence of HLA-B27 in RA has been linked to more severe disease, higher frequencies of sacroiliitis, extra-articular manifestations, and increased likelihood of persistent arthropathy.[3] The comparative studies between HLA-B27-positive and negative patients in the literature showed that HLA-B27-positive and male patients are different from HLA-B27-negative and female patients in few characters such as age at disease onset, joint involvement, disease activity, and anterior uveitis.[5]

The present study was aimed to study the significance of HLA-B27 positivity in clinical presentation and progress of the disease in rural central India.


  Materials and Methods Top


Study design

It was a prospective observational study conducted in the Department of Pathology at Mahatma Gandhi Institute of Medical Sciences, Sevagram, Maharashtra, a rural tertiary care teaching institute in Central India over the period of 24 months after clearance from the Ethics Committee of the Institute.

Patient selection

In our institute, patients presenting with joint pains are managed according to their seropositivity or negativity for serum rheumatoid arthritis factor. If it is positive, the patient is managed according to rheumatoid arthritis management guidelines. RA falls under the seronegative group of patients and they are further classified into HLA-B27-positive and HLA-B27-negative patients. Bacterial studies and culture are not a part of the clinical protocol in the management of RA in our institute because basically it is considered as an immunologic sterile disease developed after some bacterial infection, but the infection does not play a role in the treatment of this particular disorder.

HLA-B27 test was performed on the blood samples of 100 consecutive rheumatoid arthritis factor negative patients of RA presented with joint pain, by the flow cytometry method. A minimum of 1 ml of whole blood was collected aseptically by venepuncture, using ethylenediaminetetraacetic acid Vacutainer blood collection tubes. The blood collection tubes were stored up to 6 h at room temperature (20°C–25°C) until ready for staining. Once stained, samples were stable up to 24 h at 2°C–8°C. The BD™ HLA-B27 assay is a qualitative two-color direct immunofluorescence method for HLA-B27 antigen rapid detection in erythrocyte-lysed whole blood using the BD FACSCanto-II flow cytometer™.

After enrolling individual patients in case and control groups according to HLA-B27 positivity or negativity, patients were contacted on their follow-up visits. Informed consent was obtained and they were interviewed for the course of their disease. The information regarding gender and age, present complaints, history of any recent infections, type of RA, findings of clinical examinations and investigations, frequency of attacks, and duration and progress of the disease if any after primary diagnosis was collected. Clinical features were assessed by different clinical tests. Morning spinal stiffness was measured in minutes for patients with back pain. It was considered significant if it was more than 60 min duration. Schober's test is a physical examination used in physical medicine and rehabilitation and rheumatology to measure the ability of a person to flex the lower back. In lateral flexion test, >10 cm distance between fingertips to floor distance was considered as a normal value. Assessment of chest expansion with deep inspiration helps identify the side of abnormality, normally more than 5 cm is found from end of expiration to deep inspiration. The severity of arthritic pain was assessed by Rheumatoid Arthritis Severity Scale.[7] The radiographic grade of involvement of sacroiliac joint was assessed by Modified New York Criteria.[5]

Inclusion criteria

In the present study, 50 consecutive cases of HLA-B27-positive RA and 50 controls of seronegative as well as HLA B27-negative RA patients were recruited. These patients were followed up for 1–8 years' time period retrospectively and prospectively.

Exclusion criteria

Patients who were lost to follow-up or refused to give consent were included in the study.

Ethics

The prior approval was obtained from the Institutional ethics committee vide letter number MGIMS/IEC/PATH/102/2015, dated November 23, 2015. The patients were contacted in the form of interviews only at the time of their follow-up visits, after obtaining informed consent. Patient confidentiality was maintained throughout the research procedure.

Statistical analysis

The statistical analysis was performed by using descriptive (such as frequency, mean, standard deviation) and inferential statistics using Chi-square test and Student's unpaired t-test and software used in the analysis was SPSS22.0 (IBM Corp. Released 2015. IBM Statistics for Windows, Version 20.0: Armonk, New York, United States) and GraphPad PRISM 6.0 version and P < 0.05 is considered as the level of significance.


  Results Top


Out of 100 patients, 50 patients were in the study group and the rest 50 were in the control group. The maximum patients in the study group were in the age group of 21–30 years and in the control group were in the age group of 31–40 years. The mean age of the patients of study group was 32.80 ± 12.52 and of control group was 35.98 ± 14.62.

About 74% of patients in study group and 62% of control groups were males. The difference in both sexes was statistically significant in both the groups (P = 0.001 and 0.0007, respectively) [Figure 1]. Although symptomatology was more or less similar in both HLA-B27-positive (study group) and negative (control group) RA patients, the mean duration of symptoms in the study group was 22.7 ± 31.26 months and on the control group, it was 12.98 ± 6.94 months [Figure 2].
Figure 1: Gender-wise distribution of reactive arthritis in study and control groups

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Figure 2: Distribution of patients according to the duration of symptoms (months) in two groups

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The degree of illness was also not similar in all RA patients. A significant number of patients in the study group (30%) presented with the most severe arthritis, the feature which was rarely seen (6%) in HLA-B27-negative control patients and this difference was statistically significant (P = 0.007) [[Table 1], upper part]. Peripheral joints included joints of the hand, elbow, shoulder, wrist, hip, knee, and foot, while, axial joints include hyoid bone, vertebra, sacrum, and coccyx. Enthesitis is the inflammation of the enthesis, the site where tendons/ligaments insert into the bone. Enthesitis and axial skeletal involvement was seen in 66% and 86% of the study group, respectively, while it was seen in only 28% and 52% in case of control group. All of the values were statistically significant (P = 0.0001 and P = 0.0002, respectively). Peripheral joint involvement on the other hand was not significantly different in both the groups [[Table 1], middle part]. According to the radiographic grade of sacroiliac joint involvement, HLA-B27-negative patients (controls), sacroiliitis was mostly Grade 1 on radiography (68%). In case of the study group, severity was distributed almost equally in Grade 1, 2, and 3 (32%, 30%, and 26%). The difference was highly statistically significant (P = 0.0005) [[Table 1], lower part].
Table 1: Clinical features of primary reactive arthritis

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The mean morning spinal stiffness, lateral flexion, and sacroiliac compression tests showed significantly higher figures in the study group, while Schober's index and chest expansion were lower in comparison to the control group. The mean morning spinal stiffness was 34.40 ± 24.90 min in study group and 15.60 ± 18.96 min in control group (P = 0.0001); mean Schober's index was 4.91 ± 1.54 cm in study group and 5.81 ± 1.11 cm in control group (P = 0.001); mean lateral flexion was 17.26 ± 2.94 cm in study group and 11.54 ± 2.26 cm in control group (P = 0.0001); and mean chest expansion was 5.32 ± 0.93 inches in study group and 6.03 ± 0.005 inches in control group (P = 0.0001) [Figure 3].
Figure 3: Clinical features of patients with back pain in both the groups

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On follow-up visits, the severity of disease was increased in 92% of patients in the study group despite initiation of pain management, while it was decreased in 60% of patients in the control group. This difference was found to be statistically highly significant (χ2 = 58.39, P = 0.0001) [Figure 4]. The follow-up visits on three different occasions showed a significant reduction in symptoms in case of control groups, while the symptoms were either almost the same or reduced or increased in the study group. The P value was significant in case of peripheral joint involvement and enthesitis (0.0001 and 0.012, respectively), while it was insignificant in case of axial skeleton involvement (P = 0.48) [Table 2].
Figure 4: Severity of primary arthritic disease in follow-up period

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Table 2: Follow-up period

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  Discussion Top


Inflammatory arthritis developing after a distant infection has been called RA for a long, quite often depending on the microbial trigger and/or HLA-B27 status of the patient.[2] Another aspect is that HLA-B27-associated arthritis may occur identical to Reiter's syndrome with accompanying urethritis and/or conjunctivitis, whereas in the B27 nonassociated form, this has not been clearly described.[3]

The mean age of both HLA-B27-positive and negative group was more or less similar which is in correlation with other previous studies, Feldtkeller et al.,[8] Xiong et al., and Khan et al.[9] In the present study, we found that males were affected by RA significantly more than females, in both study and control groups. Similar findings have been documented in literature.[5],[10],[11] In fact, RA in female patients may represent a largely underdiagnosed and understudied disease. The reasons for this underdiagnosis could include an unbroken bias of AS being a disease of only men or differences within the disease expression in women that would cause delayed or missed diagnoses.[5]

Our patients of RA in both study and control groups presented with the arthritic symptoms of most commonly 0–20 months of duration. Leirisalo et al.[12] found no difference in the duration of the acute disease (mean 5.1 vs. 5.4 months, excluding patients with chronic disease), while Xiong et al.[5] found the median disease duration as 4 years in their study. However, this discrepancy can be explained by the fact that Xiong et al.[5] evaluated patients of more advanced disease, i.e. AS rather than RA which we have evaluated in our study. Most of our cases were in the acute phase of RA (minimum of 1-year follow-up and maximum of 8-year follow-up). With age of presentation, sex, and duration of illness, the similarities between the study group and control group ended.

One among rare studies done in India by Sonkar et al.[10] also reported that axial skeletal involvement is more in HLA-B27-positive patients, while there is no difference with respect to peripheral joint involvement in HLA-B27-positive and negative patients similar to our own findings. We found that the number of patients having higher grade of arthritic pain is significantly less in control group (6%) as compared to HLA-B27-positive group (30%). These findings are well correlated with the findings of Leirisalo et al.[12] We found that radiological severity of sacroiliitis was distributed almost equally in Grade 1, 2, and 3 in the study group (32%, 30%, and 26% respectively), while in the HLA-B27-negative group, more than two-third of the patients (68%) showed Grade 1 severity only. We found higher sacroiliitis grade on radiography with HLA B27 positive patients. Similar findings were also reported by Xiong J et al.[5] Leirisalo M et al.[12]and Ratnappa D et al.[13]

We could find only one study by Steer et al.[14] evaluating four clinical signs of back pain, i.e. morning spinal stiffness, Schober's index, lateral flexion, and chest expansion who observed findings well in correlation with our study. They observed that morning stiffness of more than 30 min duration and the sacroiliac compression test were significantly more positive in HLA-B27-positive patients with sacroiliitis (P = 0.0001 and P = 0.004, respectively). The Schober's index was significantly reduced in these patients (P = 0.0006). The results of lateral flexion test were also significant (P = 0.004). They also reported a significant decrease in chest expansion in HLA-B27-positive cases of sacroiliitis as the disease progresses from new sacroiliitis to known AS stage.

On follow-up, the overall severity of disease increased significantly in 92% of our patients in the study group despite initiation of clinical management of arthritis, while severity decreased in 60% of patients in the control group. We also found that the severity of peripheral joint pain and ethesitis were significantly reduced in the control group as compared to the study group. Leirisalo et al.[12] also observed that chronic back pain was significantly higher in HLA-B27-positive patients (P < 0.01). They also reported more systemic manifestations such as conjunctivitis, iritis, urologic symptoms, and chronic joint symptoms in follow-up studies in HLA-B27-positive patients, though not statistically significant. They also found HLA-B27-positive patients to have more frequent urologic symptoms and mucocutaneous manifestations.

In our study, we used plain X-rays to detect and to measure severity of arthritic disease which was the routine protocol in our rural hospital mainly catering economically poor patients. However, many studies show that computed tomography scan/magnetic resonance imaging might be diagnosing more and even early cases of sacroiliitis. We could not study the bacterial aspect of RA because it is not included in the management protocol at our center though it does not affect treatment in majority of these cases. These could be probable limitations of our study.

The present study was aimed at studying the influence of HLA-B27 positivity on type of RA and progress of disease in central India. Although we found a few studies from India on RA, an association of HLA-B27 is reported only in two studies: Sonkar et al.[10] and Aggarwal et al.[15] in North India.

To the best of our knowledge, this is the first study in Central India to report the significance of HLA-B27 in patients of RA with regard to its clinical presentation, management, and prognosis. As the number of cases and controls were equal, it was easier to make a comparison which was not seen in many previous studies.


  Conclusion Top


It can reasonably be concluded from the findings of the present study that HLA-B27 associated RA presents with significantly more severe primary disease and a rapid course. We recommend that HLA-B27 association should be sought in all patients of RA and positive patients must be followed more rigorously to prevent many possible complications.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Chen B, Li J, He C, Li D, Tong W, Zou Y, et al. Role of HLA-B27 in the pathogenesis of ankylosing spondylitis (Review). Mol Med Rep 2017;15:1943-51.  Back to cited text no. 1
    
2.
Cruz-Tapias P, Castiblanco J, Anaya JM. Major histocompatibility complex: Antigen processing and presentation. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, editors. Autoimmunity: From Bench to Bedside. Bogota (Colombia): El Rosario University Press; 2013. Ch. 10. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459467. [Last accessed on 2021 May 29].  Back to cited text no. 2
    
3.
Colmegna I, Cuchacovich R, Espinoza LR. HLA-B27-associated reactive arthritis: Pathogenetic and clinical considerations. Clin Microbiol Rev 2004;17:348-69.  Back to cited text no. 3
    
4.
Sheehan NJ. The ramifications of HLA-B27. J R Soc Med 2004;97:10-4.  Back to cited text no. 4
    
5.
Xiong J, Chen J, Tu J, Ye W, Zhang Z, Liu Q, et al. Association of HLA-B27 status and gender with sacroiliitis in patients with ankylosing spondylitis. Pak J Med Sci 2014;30:22-7.  Back to cited text no. 5
    
6.
Priyathersini N, Shanmugam SG, Devi SS, Chinambedu Dandapani MP, Rajendiran S, D'Cruze L. Detection of Human leukocyte antigen B27 by flowcytometry in patients with suspected ankylosing spondylitis in a tertiary care centre. Cureus 2021;13:e13560.  Back to cited text no. 6
    
7.
Bardwell WA, Nicassio PM, Weisman MH, Gevirtz R, Bazzo D. Rheumatoid arthritis severity scale: A brief, physician-completed scale not confounded by patient self-report of psychological functioning. Rheumatology (Oxford) 2002;41:38-45.  Back to cited text no. 7
    
8.
Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int 2003;23:61-6.  Back to cited text no. 8
    
9.
Khan MA, Khan MK, Kushner I. Survival among patients with ankylosing spondylitis: A life-table analysis. J Rheumatol 1981;8:86-90.  Back to cited text no. 9
    
10.
Sonkar GK, Usha, Singh S. Is HLA-B27 a useful test in the diagnosis of juvenile spondyloarthropathies? Singapore Med J 2008;49:795-9.  Back to cited text no. 10
    
11.
Niederer R, Danesh-Meyer H. Uveitis screening: HLAB27 antigen and ankylosing spondylitis in a New Zealand population. N Z Med J 2006;119:U1886.  Back to cited text no. 11
    
12.
Leirisalo M, Skylv G, Kousa M, Voipio-Pulkki LM, Suoranta H, Nissilä M, et al. Followup study on patients with Reiter's disease and reactive arthritis, with special reference to HLA-B27. Arthritis Rheum 1982;25:249-59.  Back to cited text no. 12
    
13.
Rantapää Dahlqvist S, Nordmark LG, Bjelle A. HLA-B27 and involvement of sacroiliac joints in rheumatoid arthritis. J Rheumatol 1984;11:27-32.  Back to cited text no. 13
    
14.
Steer S, Jones H, Hibbert J, Kondeatis E, Vaughan R, Sanderson J, et al. Low back pain, sacroiliitis, and the relationship with HLA-B27 in Crohn's disease. J Rheumatol 2003;30:518-22.  Back to cited text no. 14
    
15.
Aggarwal A, Misra R, Chandrasekhar S, Prasad KN, Dayal R, Ayyagari A. Is undifferentiated seronegative spondyloarthropathy a forme fruste of reactive arthritis? Br J Rheumatol 1997;36:1001-4.  Back to cited text no. 15
    


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