Increased frequency of HLA-B7 among B27-negative seronegative spondarthritis patients from Mumbai, western India

British Journal of Biomedical Science, 2009 by Devraj, J P, Shankarkumar, U, Ghosh, K

ABSTRACT

Seronegative Spondarthritis (SSA) is a group of inflammatory disorders that shares certain clinical features and has a strong association with the human leucocyte antigen (HLA)-B27 allele. Serologically, HLA-B27, HLA-B22, HLA-B7, HLA-B40 and HLA-B42 antigens belong to the HLA-B cross-reacting antigen group (CREG). In addition to B27, other B locus antigens are associated with B27-negative American black, Brazilian, French and Chinese SSA patients. Many B27-negative individuals in India have developed SSA with severe clinical and radiological findings. This stimulated the evaluation of the involvement of HLA-B7 CREG antigens among B27-negative SSA patients from western India. A total of 276 SSA patients who were B27-negative and fitted the modified New York criteria for AS and the European Spondyloarthropathy Study Group (ESSG) criteria for Spondarthritis from western India were studied and compared with 637 normal, healthy individuals who were B27-negative and of the same ethnic background. A significantly increased phenotype frequency of HLA-B7 (PF=57.24% vs. 22.44%; P

KEY WORDS: HLA-B7 antigen.

HLA-B22.

HLA-B27 antigen.

HLA-B40 antigen, human.

HLA-B42 antigen, human.

Spondylitis.

Introduction

Seronegative Spondarthritis (SSA) is a group of diseases that includes mainly ankylosing spondylitis (AS), Reiters syndrome/reactive arthritis (ReA), enteropathic spondylitis (Crohn's disease and ulcerative colitis), psoriatic arthropathy (PsA) and undifferentiated spondylitis (uSp).1

Ankylosing spondylitis is a chronic inflammatory disease that begins primarily in the sacroiliac joints and goes on to involve the spine and other large joints.1 An association between human leucocyte antigen (HLA)-B27 and AS was first reported in 1973," and an association with other members of the SSA group was confirmed later.4-7 Furthermore, it is suggested that the other HLA-B locus alleles are also involved in B27-positive and -negative SSA patients around the world.

Human leucocyte antigens are highly cross-reactive in nature and share an amino acid sequence for most of their molecular structure. Antibodies bind to specific sites on these molecules and it would be expected that many different antigens would share a site (epitope) to which a specific antibody will bind. Thus cross-reactivity is the sharing of epitopes between antigens, and the term crossreacting groups (CREGs) is often used in this respect.

Serological HLA typing has shown that there are many CREGs and they have been reported among the antigens of the HLA A, HLA B and HLA DR loci. The CREGs of HLA antigens can be strong or weak, depending on the antigen-antibody binding. The HLA-B27 CREG antigens, which include HLA-B27, -B7, -B22, -B40 and -B42, are very strong.

Khan et al. found an association between HLA-B7 CREG antigens and AS among American black patients.8-9 Subsequently, these findings were confirmed in ReA patients with AS by Arnet.10 Later, Benchetrit showed an association between HLA-B7 and -B22 and ReA in patients from Israel.11 Similarly, HLA-B7 CREG antigens have been associated with Brazilian uSpA patients,12 and an association between HLA-B7 and inflammatory arthritis has been reported in patients from France.13

The association of HLA-B40 with AS was reported by Robinson and colleagues who found that HLA-B60 was increased in B27-positive AS patients.14 In another study, Cedoz reported that HLA-B40 is associated with prominent peripheral arthritis.12 Subsequently, Brown and colleagues demonstrated that HLA-B60 is associated with AS both in B27-positive and B27-negative individuals.15 Recently, in a study of a Taiwan Chinese population, it has been reported that HLA-B60 and HLA B-61 (splits of HLA-B40) are strongly associated with HLA-B27-negative AS patients.16

Previous reports show that the prevalence of B27 in a western Indian population with SSA is 30-80%.5-7 Recently, however, we observed that a higher number of B27-negative individuals develop SSA with typical clinical and radiological findings. Thus, we hypothesise that these patients must be carrying one of the B27 CREGs (B7, B22, B40 and B42). Therefore, the present study aims to discover whether or not other antigens are involved in HLA-B27-negative Spondarthritis patients in western India.

Materials and methods

Selection criteria for patients and controls

A total of 276 HLA-B27-negative patients were selected according to the revised New York criteria for AS17 and the European Spondyloarthropathy Study Group (ESSG) criteria for SSA between April 2004 and March 2007. 18 Patients include those who were suffering from arthritis and satisfied at least four of the following criteria: insidious onset, duration >3 months, radiological bilateral or unilateral sacroiliitis, limitation of motion of the lumbar spine and chest expansion, and association with morning stiffness that improves with exercise and is not relieved by rest. All patients were negative for rheumatoid factor.

Clinical evaluation was undertaken by rheumatologists at various hospitals around Mumbai, and cases were also reevaluated by one of the authors (KG). The patients underwent various tests including X-ray (affected joints, sacroiliac joints, lumbar and cervical spine) full blood count with ESR and rheumatoid factor.

The study was approved by the local ethics committee. The control group (from the same socioeconomic and ethnic background) comprised 637 age- and gender-matched healthy individuals who were negative for B27.