Association Of HLA-B27 Research Articles

The influence of natural ERAP1 polymorphism on the HLA-B27 peptidome in vivo

The joint association of HLA-B27 and ERAP1 with ankylosing pondylitis (AS) suggests that the functional interaction between oth proteins may be critical to AS pathogenesis. The involvement f ERAP1 in the N-terminal trimming of peptides to their optimal ize for binding to MHC-I molecules further suggests that it may ffect the pathogenetic role of HLA-B27 by influencing the genration of specific epitopes, through a more general effect on the eptidome, which might influence the whole biological behavior f HLA-B27, or both. The present study was designed to assess eneral effects of natural ERAP1 polymorphism on the HLA-B27 eptidome. To this end we isolated the HLA-B27-bound peptide ools from several human cell lines expressing the same subtype B*27:04), but different natural variants of ERAP1, and compared hesizedistributionandothermolecular featuresofpeptides showng cell-dependent expression differences. Three pairwise comparisons of the HLA-B27 peptidomes isoated from cell lines expressing ERAP1 variants with different ombinations of AS-associated amino acid changes were carried ut by mass spectrometry, which also allowed us to estimate the elative expression levels of shared peptides among cell lines. Diferences in the expression and size of many peptides were found, hich were dependent both on the ERAP1 context and the Nerminal sequence features of the ligand precursors, but not on he internal sequence of the B27 ligands. The pattern strongly sugested significant differences in enzymatic activity among natural RAP1 variants. In addition, theHLA-B27molecule expressed in the ontext of the less active ERAP1 allotype showed lower thermostaility than all others. Our results indicate that: 1) ERAP1 polymorphism has a signifcant influence on the HLA-B27 peptidome through affecting the uantitative expression of many peptides: less active ERAP1 varints tend to favor longer peptides and to disfavor shorter ones, 2) hemolecular determinants of this influence are likely based on the usceptibility of the N-terminal sequence of the peptide precursors o ERAP1-mediated trimming, and 3) below a certain threshold of RAP1 activity, the effects on the peptidome result in decreased LA-B27 stability. This study is the first to show the effect of natual ERAP1 polymorphismon theHLA-B27 peptidome in vivo, and to uggest a mechanism for the functional interaction between these womolecules,which is likely to influence both in the pathogenesis f AS and other ERAP1/MHC-I associated diseases.

Comparison of Enteropathic Spondyloarthritis and Ankylosing Spondylitis(Differences in the Clinical Characteristics, Complaints and Gender)

Objectives: To assess differences in patients with Ankyosing Spondylitis (AS) and Enteropathic Spondyloarthritis (ESpA) with regards to musculoskeletal symptoms at presentation and the main musculoskeletal problems during the disease course. The patients’ demographic data and clinical characteristics were also compared. Methods: Following clinical assessment, patients with AS and ESpA were asked to respond to a validated screening questionnaire, choosing from a list of seven musculoskeletal symptoms potentially present at disease onset (back pain, neck pain, shoulder pain, hip pain, knee pain, buttock pain, and foot pain) and another seven symptoms known to be associated with SpAs (fatigue, neck pain, upper back pain, lower back pain, stiffness, joint pains/swelling, and pain with pressure [enthesitis]). More than one symptom could be reported by each patient. Results: In total, 124 patients were included in the study. They were 84 patients diagnosed with AS (M:F = 41:43 or 48.8%:51.2%; age = 43.4 ± 12.8 years), and 40 patients had ESpA (M:F = 9:31 or 22.5%:77.5%; age [mean ± SD] = 49.6 ± 14.1 years). In the ESpA group there were included 12 patients with Crohn’s disease and 28 patients with ulcerative colitis. The two groups had similar disease profiles, with the only exceptions the delay in diagnosis, which was significantly shorter for ESpA than for AS (P < 0.05), and enthesitis pain, which was significantly greater for ESpA than for AS (P < 0.05). Only two patients were HLA-B27+ in the ESpA group (7.1% of those tested) compared with 37.7% in the AS group. ESpA patients had more peripheral disease at presentation (knees, feet, shoulders) than the AS patients, although both groups reported back pain as the main symptom at disease onset (57% with entero SpA and 70% with AS). ESpA patients continued to report joint pains as the main problem during the disease course (68.6% versus 44.9% in AS patients) compared with low back pain reported as the main problem by AS patients (57.1% for ESpA and 70.5% for AS). Conclusion: ESpA patients had more peripheral disease at presentation and during the disease course than AS patients, a shorter delay in diagnosis, more enthesitis, and no HLA-B27 association.

Reactive arthritis: advances in diagnosis and treatment

Reactive Arthritis (ReA) is an aseptic synovitis developing after a primary infection distant from the joint, mainly localized in the gastrointestinal (Enteroarthritis) or genitourinary tract (Uroarthritis). Because of either the asymmetric joint involvement, the possibility of involvement of the spine and enthesis, and the HLA-B27 association ReA is considered one of the spondylarthropathies. Recently, bacterial components or viable bacteria were found in joints during ReA. For this reason, the limits between ReA itself and infectious arthritis are now less definite. Generally accepted diagnostic and classification criteria are still lacking but the improvement in techniques for detection of bacteria increase the possibility to identify the triggering agents. Several studies have examined the role of antimicrobial drugs in ameliorating the natural course of ReA, with some positive results for Uroarthritis only. However, more conventional treatments based on NSAIDs, sulfasalazine and steroids are effective in many cases.

HLA-B27 association with uveitis in an Asian Indian population.

Uveitis refers to diseases characterized by intraocular inflammation of the uveal tract. Anterior uveitis is a common ocular disease characterized by inflammation of the iris and the ciliary body. To establish the frequency of HLA-B27-positive uveitis in Asian Indian population, study their clinical profile and compare it with other reports in literature. We retrospectively reviewed medical data of 89 patients of uveitis referred for HLA B27 typing with predominantly ocular symptoms during the period from April 2006-October 2010. All patients were tested for complete blood count, erythrocyte sedimentation rate, infectious diseases serology, HLA-B27 typing, and prepared radiographs of the sacroiliac joints and lumbar spine if required. The HLA-B27 positive rate was 56.2% among patients and 3% for control samples. Most of the patients were in the age group of 41-50 years with a male predominance. HLA-B27 was seen to be associated with acute anterior uveitis in Asian Indian males and the test is important for confirmation of diagnosis, prognostication and also for planning the treatment.

The role of ERAAP polymorphisms in the autoimmune disease Ankylosing Spondylitis (100.17)

Abstract Ankylosing spondylitis (AS) is a chronic inflammatory joint disease of the axial skeleton, ultimately leading to fusion of the spine. For over three decades it has been known that the MHC class I molecule HLA-B27 is strongly associated with AS. In addition, the ER-resident aminopeptidase ERAAP (or ERAP1) was recently shown to be associated with as much as 26% of the risk for developing AS in HLA-B27 positive individuals. Multiple non-synonymous SNPs have been identified in the ERAAP gene that increase the risk of AS, but the functional significance of these polymorphisms is not known. The ERAAP protease is an essential component of the MHC class I pathway where it trims antigenic peptides in the ER. The significant association of both HLA-B27 and ERAAP with AS suggests that an altered MHC class I antigen processing pathway could play an important role in this partially T cell-mediated disease. To test this hypothesis we have analyzed the antigen processing capacity of several polymorphic forms of human ERAAP in ERAAP-deficient cells. All the polymorphic ERAAP constructs tested were enzymatically active and able to trim model antigenic peptides in different cell lines, with either no or minor differences in the quantity of total epitopes generated. We will discuss the implications of these findings.

An Update on the Genetics of HLA B27-associated Acute Anterior Uveitis

The discovery of the association of HLA B27 with spondyloarthropathy led to more questions than answers about the role of this gene in disease susceptibility. The realization that HLA B27 was not responsible for all of the genetic effects helped to lay a foundation for further investigation into the genetics of uveitis. Over several decades, genetic findings have provided clues to advance the understanding of mechanisms of uveitis and to catalyze new research on diagnostics, animal models, and therapies. From the early candidate gene studies on immune mediators to the recent genome-wide investigations, much has been discovered. However, these discoveries have come with the caveat that a genetic finding does not automatically reveal the disease-relevant functional effect of the associated variant.

Mutational Analysis Reveals a Complex Interplay of Peptide Binding and Multiple Biological Features of HLA-B27

Molecular polymorphism influences the strong association of HLA-B27 with ankylosing spondylitis through an unknown mechanism. Natural subtypes and site-directed mutants were used to analyze the effect of altering the peptide-binding site of this molecule on its stability, interaction with tapasin, folding, and export. The disease-associated subtypes B*2705, B*2702, and B*2704 showed higher thermostability at 50 °C than all other subtypes and mutants, except some mimicking B*2702 polymorphism. The lowest values were found among pocket B mutants, most of which interacted strongly with tapasin, but otherwise there was no correlation between thermostability and tapasin interaction. Mutants resulting in increased hydrophobicity frequently acquired their maximal thermostability faster than those with increased polarity, suggesting that this process is largely driven by the thermodynamics of peptide binding. Folding, export, and tendency to misfold were influenced by polymorphism all along the peptide-binding site and were not specifically dependent on any particular region or structural feature. Frequent uncoupling of thermostability, folding/misfolding, and export can be explained by the distinct effect of mutations on the acquisition of a folded conformation, the optimization rate of B27-peptide complexes, and their quality control in the endoplasmic reticulum, all of which largely depend on the ways in which mutations alter peptide binding, without excluding additional effects on interactions with tapasin or other proteins involved in folding and export. The similarity of the generally disease-associated B*2707 to nondisease-associated subtypes in all the features analyzed suggests that molecular properties other than antigen presentation may not currently explain the relationship between HLA-B27 polymorphism and ankylosing spondylitis.

Genetics of ankylosing spondylitis

Over the past 3 years, several new genes and gene deserts have been identified that are associated with ankylosing spondylitis (AS). The purpose of this review is to discuss the major findings of these studies, and the answers they provide and questions they raise about the pathogenesis of this common condition. Five genes/genetic regions have now definitively been associated with AS [the major histocompatibility complex (MHC), IL23R, ERAP1, 2p15 and 21q22]. Strong evidence to support association with the disease has been demonstrated for the genes IL1R2, ANTXR2, TNFSF15, TNFR1 and a region on chromosome 16q including the gene TRADD. There is an overrepresentation of genes involved in Th17 lymphocyte differentiation/activation among genes associated with AS and the related diseases inflammatory bowel disease and psoriasis, pointing strongly to this pathway as playing a major causative role in the disease. Increasing information about differential association of HLA-B27 subtypes with disease suggests a hierarchy of strength of association of those alleles with AS, providing a useful test as to the validity of different potential mechanisms of association of HLA-B27 with AS. The mechanism underlying the association of the gene deserts, 2p15 and 21q22, suggests the involvement of noncoding RNA in AS etiopathogenesis. The increasing list of genes identified as being definitely involved in AS provides a useful platform for hypothesis-driven research in the field, providing a potential alternative route to determining the underlying mechanisms involved in the disease to research focusing on HLA-B27 alone.

Genetics and genomics of ankylosing spondylitis

Ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the pathogenesis of which is poorly understood. The mechanism by which the main gene for the disease, HLA-B27, leads to AS is unknown. Genetic and genomic studies have demonstrated involvement of the interleukin-23 (IL-23) signaling pathway in AS, a finding which has stimulated much new research into the disease and has led to therapeutic trials. Several other genes and genetic regions, including further major histocompatibility complex (MHC) and non-MHC loci, have been shown to be involved in the disease, but it is not clear yet how they actually induce the condition. These findings have shown that there is a strong genetic overlap between AS and Crohn's disease in particular, although there are also major differences in the genes involved in the two conditions, presumably explaining their different presentations. Genomic and proteomic studies are in an early phase but have potential both as diagnostic/prognostic tools and as a further hypothesis-free tool to investigate AS pathogenesis. Given the slow progress in studying the mechanism of association of HLA-B27 with AS, these may prove to be more fruitful approaches to investigating the pathogenesis of the disease.

Association of various inflammatory diseases with human leukocyte antigens B27, B7, Bw4 and Bw6 in patients with SSA

Seronegative spondyloarthropathies (SSA) are a group of inflammatory disorders, which clinically involve the axial skeleton and the sacroiliiac and shoulder joints. The aim of the present study was to study the association of HLA B27, B7, Bw4 and Bw6 with some inflammatory diseases, in SSA patients in our area. A total of 220 SSA patients were studied and HLA typing for these antigens were done by the complement-mediated microcytotoxicity method. The total positivity of B27 was found to be 68.64% in SSA patients. Tubercular infection (chi(2) = 8.06) and acute anterior uveitis (chi(2) = 6.19) were found to be statistically significant (P < 0.05) in B27-positive SSA patients. Tuberculosis was also found to be significantly (chi(2) = 6.40) associated with Bw4. In SSA urinary tract infection, gastrointestinal infection and streptococcal infection were not significantly associated with B27, B7, Bw4 or Bw6 antigens. Our study concludes that microbial infections do have some pathogenic role in causing SSA.

Microbial antigens mediate HLA-B27 diseases via TLRs

HLA-B27 positive individuals are predisposed to reactive arthritis developing 1–3 weeks after urogenital and gastrointestinal infections. Also ankylosing spondylitis (AS) associates strongly to HLA-B27, but no specific infection, Klebsiella pneumoniae excluded, has been linked to it. Before the discovery of its HLA-B27 association there were many reports suggesting a link between chronic prostatitis in men or pelvic inflammatory disease in women and AS. They have since been forgotten although HLA-B27 did not help to understand, why this disease has an axial and ascending nature. It is proposed that the urogenital organs form a source of damage (or danger)-associated molecular patterns (DAMPs), either exogenous pathogen-associated molecular patterns (PAMPs) from microbes or endogenous alarmins, such as uric acid, released from necrotic cells or urate deposits. DAMPs are slowly seeded from low-down upwards via the pelvic and spinal lymphatic pathways. They reach Toll-like receptors (TLRs) in their target mesenchymal stem cells, which are stimulated to ectopic enchondral bone formation leading to syndesmophytes and bamboo spine. At the same time inflammatory cytokines induce secondary osteoporosis of the spine. This new paradigm places microbes, HLA-B27 and TLRs in the pathogenic centre stage, but without pinpointing any (one) specific pathogen; instead, shared microbial patterns are indicated.

HLA-B27 predicts a more extended disease with increasing age at onset in boys with juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is a heterogeneous condition with very few clinical and laboratory signs that can help predict the course and severity of the disease in the individual patient. The cell-surface antigen HLA-B27 is well known to be associated with spondyloarthropathies, reactive arthritis, and enthesitis. HLA-B27 plays an important role in the classification of JIA, since evidence of sacroiliitis most often evolves after years of arthritis in other joints. We investigated the associations of HLA-B27 and the clinical manifestations of JIA using a method as close to a population-based study as possible. We studied an incidence-based cohort of 305 patients collected prospectively in 3 Nordic countries (Sweden, Norway, Denmark). Clinical and serological data of the first 3 years of the disease were collected. HLA-B27 was found to be positive in 25.5% of the patients, and we found a higher proportion of HLA-B27-positive boys with older age at disease onset (p=0.034). Regression analysis showed a correlation of 0.7 in the HLA-B27-positive boys, pointing to a higher risk of more joint involvement with older age at disease onset. By Fisher's exact test, involvement of small joints in the lower extremities was associated with HLA-B27 in boys (p=0.011), but not in girls (p=0.687). HLA-B27 was associated with inflammatory back pain in both sexes (p=0.041 in boys, p=0.042 in girls), but with enthesitis only in boys (p<0.001 in boys, p=0.708 in girls). HLA-B27 is of increasing importance with older age at disease onset in boys with JIA, predicting more active joints within the first 3 years of disease, and also involving small joints in the lower extremity to a greater degree than in HLA-B27-negative boys. During the first 3 years of disease the occurrence of HLA-B27 is associated with inflammatory back pain in both sexes, but with enthesitis only in boys. Our data present new challenges for the ILAR classification of JIA.

A functional polymorphism of the vasoactive intestinal peptide receptor 1 gene correlates with the presence of HLA-B *2705 in Sardinia

The association of HLA-B27 with ankylosing spondylitis (AS) is the strongest among all inflammatory diseases. However, the exact role of these molecules in disease pathogenesis is still unknown. The existence of HLA-B27 variants rarely found in patients introduces a further level of complexity. It is now accepted that other genes of minor impact contribute to modify disease susceptibility and these genes might be diverse in different populations depending on the genetic background. We report here a study performed in Sardinia, an outlier population in which two major HLA-B27 subtypes are present, B (*)2705 strongly associated with AS and B (*)2709 which is not, and show the co-occurrence of the B (*)2705 allele with a single nucleotide polymorphism (SNP) mapping at 3'-UTR of the receptor 1 (VIPR1) for the vasoactive intestinal peptide (VIP), a neuropeptide with anti-inflammatory properties. This same SNP is associated with a different kinetics of down-modulation of the VIPR1 mRNA in monocytes after exposure to lipopolysaccharide (P=0.004). This particular setting, HLA-B (*)2705 and a functional polymorphism in VIPR1 gene, might be due to a founder effect or might be the result of a selective pressure. Irrespectively, the consequent downregulation of this receptor in the presence of a 'danger' signal might influence susceptibility to AS.

HLA and Non-HLA Genes in Ankylosing Spondylitis and Seronegative Spondyloarthritis in Asia

Genetic susceptibility to ankylosing spondylitis, the prototype of the seronegative spondyloarthropathies is strongly associated with the major histocompatibility antigen HLA-B27. However besides HLA-B27, there are other genes, both MHC and non-MHC, that predispose to susceptibility and severity of disease. Studies on the genetic epidemiology of these diseases in Asia have shown similar findings to those elsewhere; with most showing strong association of HLA-B27 with ankylosing spondylitis, no difference in HLA B27 subtypes between patients and controls, some association of IL-1 gene cluster, TNF and LMP polymorphisms with ankylosing spondylitis, association of HLADR8 with acute anterior uveitis, and no association with TAP and TGF polymorphisms. Genetic predisposition to disease severity has not been reported from Asian studies. As most studies from the region have been of small sample size, future studies should be designed to obtain adequate levels of significance, and the results of genome wide linkage scans may be useful in guiding future studies into the genetic background of these diseases.

The pathogenesis of ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory disease that can cause significant functional complications by affecting the sacroiliac joints and axial skeleton. Despite a longstanding knowledge about the familial associations of this disease, particularly among patients positive for human leukocyte antigen (HLA)-B27, the fundamental pathogenetic mechanism by which this disease arises in genetically susceptible individuals remains ill defined. Furthermore, the molecular predilection for characteristic articular site involvement remains under ongoing investigation. Current theories about the HLA-B27 association range from the presentation of novel arthritogenic peptides, to abnormal autoimmune stimulation, to anomalous microbial tolerance. The immune effectors of this damage include CD4+, CD8+, and natural killer cells, with marked heterogeneity at different sites. Biomechanical stresses may trigger this disease by exposing the body to previously immune-sequestered autoantigens or by providing a route for bacterial seeding. Environmental triggers such as infection have not been definitively established but may represent a primary pathogenic step in a molecular-mimicry process. In this article, the authors review the current literature on the origin and pathophysiology of AS, focusing on genetic and molecular associations, consequent pathomechanisms, and associated triggers. An improved understanding of the sequence of molecular events that predispose and initiate the onset of this disease will allow for more specific and targeted therapy and better avoidance of the significant side effects of systemic immunomodulation.

CD8+ T cells from SIV elite controller macaques recognize Mamu-B*08-bound epitopes and select for widespread viral variation.

BackgroundIt is generally accepted that CD8+ T cell responses play an important role in control of immunodeficiency virus replication. The association of HLA-B27 and -B57 with control of viremia supports this conclusion. However, specific correlates of viral control in individuals expressing these alleles have been difficult to define. We recently reported that transient in vivo CD8+ cell depletion in simian immunodeficiency virus (SIV)-infected elite controller (EC) macaques resulted in a brief period of viral recrudescence. SIV replication was rapidly controlled with the reappearance of CD8+ cells, implicating that these cells actively suppress viral replication in ECs.Methods and FindingsHere we show that three ECs in that study made at least seven robust CD8+ T cell responses directed against novel epitopes in Vif, Rev, and Nef restricted by the MHC class I molecule Mamu-B*08. Two of these Mamu-B*08-positive animals subsequently lost control of SIV replication. Their breakthrough virus harbored substitutions in multiple Mamu-B*08-restricted epitopes. Indeed, we found evidence for selection pressure mediated by Mamu-B*08-restricted CD8+ T cells in all of the newly identified epitopes in a cohort of chronically infected macaques.ConclusionsTogether, our data suggest that Mamu-B*08-restricted CD8+ T cell responses effectively control replication of pathogenic SIVmac239. All seven regions encoding Mamu-B*08-restricted CD8+ T cell epitopes also exhibit amino acid replacements typically seen only in the presence of Mamu-B*08, suggesting that the variation we observe is indeed selected by CD8+ T cell responses. SIVmac239 infection of Indian rhesus macaques expressing Mamu-B*08 may therefore provide an animal model for understanding CD8+ T cell-mediated control of HIV replication in humans.

HLA Association in Seronegative Spondyloarthritis Patients From Mumbai, India

Seronegative spondyloarthropathies (SSA) are a group of inflammatory disorder, which clinically involves axial skeleton, sacroiliac and shoulder joints. These patients often complain of low back pain with prominent morning stiffness or nocturnal pain. The association of HLA-B27 allele and its novel subtypes with spondyloarthropathy remains one of the best examples of a disease association with a hereditary marker. The study population comprises of 6180 suspected SSA patients who were referred to the HLA Laboratory of Sir Hurkisandas Nurrotumdas. Hospital, Mumbai, India, from September 1985 to May 2005, for their HLA antigen profile. These were compared with 5000 ethnically matched control group whose HLA typing was performed during the same period by the standard NIH microlymphocytotoxicity assay using commercially available sera, defining a single HLA specificity. Our results revealed that HLA-B27 (8.49% vs. 2.37%) is significantly associated with SSA when compared to controls. Among the B7 CREG alleles such as HLA-B7, HLA-B40, HLA-B22 and HLA B42, the HLA-B7 (10.14% vs. 2.42%) and HLA B-40 (10.28% vs. 5.03%) allele frequencies were significantly increased among the HLA-B27 negative patients when compared to the HLA-B27 positive patients. HLA B27 allele distribution among the different caste and population groups revealed that maximum allele frequencies were observed among the Gujarathi and Maharastrians with distinctive variations among the caste groups studied and reported from India. Our results confirm the HLA B27 association in SSA patients, but the strength of this association varies considerably between racial and ethnic groups. Further, HLA-B7 and HLA B-40 alleles may also be associated with HLA-B27 negative patients with clinical symptoms of spondyloarthropathy.

Presence of spondyloarthropathy and its clinical profile in patients with hypoparathyroidism

Though spondyloarthropathy has been described in patients with sporadic idiopathic hypoparathyroidism (SIH), the clinical profile is not known. To describe the clinical profile including radiological features of spondyloarthropathy and prevalence of HLA-B27 allele in patients with hypoparathyroidism, and to identify any differences from ankylosing spondylitis. Clinical characteristics and radiographs of pelvis and spine were assessed in 40 consecutive patients with SIH. Radiographs were assessed by radiologist (RS) and rheumatologist (RG) for the features of spondyloarthropathy including sacroiliitis, syndesmophytes and hip joint calcification, and so on. HLA-B27 genotyping was carried out in patients with SIH, and 195 healthy controls using duplex PCR. Fourteen control radiographs were from age-matched normal individuals. Three patients with SIH had clinically overt spondyloarthropathy which closely resembled ankylosing spondylitis. Fourteen (eight females and six males) of the 40 patients with SIH showed radiological changes including syndesmophytes in lower dorsal or dorso-lumbar spine (n = 6), sacroiliitis and new bone formation at the acetabular rim of the hip joint (n = 10). Though all six patients demonstrating syndesmophytes had new bone formation at hip, sacroiliitis was seen in only three of them. None of the 14 controls had syndesmophytes, sacroiliitis or hip joint calcification. The mean (SD) duration of illness (15.4 +/- 8.7 vs. 6.5 +/- 5.9 years, P < 0.01), BMI (24.1 +/- 5.2 vs. 20.8 +/- 3.7 kg/m(2), P = 0.04) and frequency of basal ganglia calcification was higher (100%vs. 57.7%, P < 0.01) in patients who showed changes of spondyloarthropathy in comparison to those without these changes. On multiple logistic regression analysis, only duration of hypoparathyroid illness was associated with spondyloarthropathy with an odds ratio of 1.17 (95% CI = 1.05-1.30, P < 0.01) per year increase in the duration. The mean age, serum total calcium, inorganic phosphorus and serum intact PTH (iPTH) levels were not significantly different between SIH patients with and without spondyloarthropathy. The frequency of HLA-B27 allele was comparable between SIH and the control groups. Thus, spondyloarthropathy is a distinct clinical entity in patients with SIH. Its salient clinical features include presence of syndesmophytes at the thoracic or thoraco-lumbar spine, mild sacroiliitis, calcification at the acetabular margin of hip, preserved bone density, equal distribution in both sexes and lack of HLA-B27 association. Presence of spondyloarthropathy, like basal ganglia calcification, is associated with longer duration of hypoparathyroidism. It is important to differentiate hypoparathyroid-related spondyloarthropathy from ankylosing spondylitis because the management for the two disorders is different.

Seronegative Spondyloarthropathy – Studies from the Asia Pacific Region

Recent therapeutic advances, in particular the use of anti-tumour necrosis factor (anti-TNF) agents, have revived interest in the seronegative spondyloarthropathies (SpA), a group of arthritides characterised by axial skeletal involvement and the absence of rheumatoid factor. The purpose of this article is to review the studies that have been done in the Asia Pacific region, as a broad understanding of the scope and severity of this group of diseases would enable rheumatologists and physicians in this part of the world to better manage their patients. The majority of genetic studies have focused on the associations of HLA-B27 with ankylosing spondylitis (AS) and SpA, while a few studies examined the associations of the CARD, IL-1, LMP2, TAP and TGF with AS. There are a handful of studies on the immunological responses to bacteria and cytokine levels in AS. The onset and clinical features of SpA have been reported from most countries in the region, but no data on patient outcomes, using current measurement tools such as the Bath Ankylosing Spondylitis Disease Activity index (BASDAI), is available. Validation of these instruments of measurement as well as classification criteria in different ethnic populations is necessary where no prior data exist. Future studies will likely be focused on better clinical characterisation of patient cohorts, particularly with regard to the use of currently used measurement tools for disease activity and spinal function and mobility, and the identification of the need for biologic therapy in each country.

Major histocompatibility genes and ankylosing spondylitis

The association of HLA-B27 with ankylosing spondylitis accounts for nearly 40% of the total disease risk. However, fewer than 5% of B27-positive individuals in the general population become affected. Genomewide scans suggest that other major histocompatibility complex genes further heighten this risk, although linkage disequilibrium with HLA-B27 has confounded their precise identification. Over 31 variants of HLA-B27 have been identified to date, which have evolved from the original B27 allele (B*2705) along three geographic lines. HLA-B*2705 and B*2702 are the primary subtypes in Caucasians with spondylitis, and B*2704 and B*2707 are the primary subtypes in Asians. HLA-B*2706 and B*2709 are not disease associated. There are four theories of how HLA-27 causes spondyloarthritis: (1) HLA-B27 presents a bacterially derived 'arthritogenic peptide' (not yet identified); (2) misfolding or homodimerization of HLA-B27 heavy chains results in a pro-inflammatory response; (3) HLA-B27-positive individuals have deficient intracellular killing of arthritogenic organisms; and (4) HLA-B27 itself, due to sequence homology with bacterial proteins, becomes autoantigenic.