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... Similar rates of AS were reported among Americans, Europeans and other ethnic groups (for example Han Chinese) that have similar HLAB27 status. Populations with a low frequency of HLAB27 (for example Japanese people) demonstrate the lowest frequencies of AS. 28,45, AS is less frequent among African Americans compared with white people in the uSA and is also considered to be rare in SubSaharan Africa (Figure 3) , suggested to reflect the low prevalence of HLAB27 in African populations.  However, this hypothesis has been partly challenged by data concerning a particular West African population where AS was rare but the frequency of HLAB27 was found to be similar to that in most white populations. ...
The accumulative global burden of autoimmune and inflammatory rheumatic diseases is substantial. Studying the distribution of these conditions across various global regions and ethnic groups by means of geoepidemiology might readily provide epidemiological data and also advance our understanding of their genetic and environmental underpinnings. In order to depict the geoepidemiology of autoimmune and inflammatory rheumatic diseases, namely rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, ankylosing spondylitis and Sjögren's syndrome, we present a comprehensive collection of epidemiological reports from various world regions, including the prevalence of each of these conditions. The accumulated data show that the reviewed rheumatic diseases are global phenomena, and, with some variance, seem to be relatively evenly distributed. This finding is in contrast with the obviously uneven distribution of some major nonrheumatic autoimmune conditions. In addition, geoepidemiology demonstrates that ethnogenetic susceptibility interacts with lifestyle and environmental factors, which include socioeconomic status, infectious agents (triggering or protective agents), environmental pollutants, and vitamin D (dependent on sunlight exposure), in determining the risk of developing rheumatic autoimmunity.
The HLA-B27 antigen is an important genetic marker in ankylosing spondylitis (AS). Methods for the detection of B27 include the microlymphocytotoxicity test and, more recently, flowcytometry (FC). Here, we describe a new method, IMS-ELISA, for measuring the B27-antigen. It combines immunomagnetic separation (IMS), to obtain B27-positive cells from whole blood samples, with an enzyme-linked immunosorbent assay (ELISA) as a read-out. IMS-ELISA was tested on 367 samples obtained from five different hospitals in Taiwan. The sensitivity, specificity and accuracy of the method were compared with FC. Any conflicting data between IMS-ELISA and FC was confirmed by HLA-DNA typing via PCR-SSP (polymerase chain reaction-sequence specific primers). Overall, the results for sensitivity, specificity and accuracy obtained by IMS-ELISA and FC did not show any significant difference (p>0.05). However, when considering laboratory time, cost, ease of operation and the screening of large samples for HLA-B27, the IMS-ELISA was superior to the FC method. We conclude that IMS-ELISA may be used as a fast screening method for HLA B27 detection.
... These common features include: (1) male sex preponderance; (2) arthritic involvement of the axial skeleton (e.g., sacroiliac joints); (3) extra-articular musculoskeletal involvement (e.g., bursitis, enthesitis); and (4) extra-articular (e.g., ocular, genito-urinary) inflammation. In both white [36-38] and American Indian patients [39-43], the human class I histocompatibility complex antigen HLA-B27 constitutes a strong risk factor [44-47]. ...
High prevalence rates for rheumatoid arthritis, spondyloarthopathies, and systemic lupus erythematosus have been described in American Indian and Alaskan Native adults. The impact of these diseases on American Indian children has not been investigated.
We used International Classification of Diseases-9 (ICD-9) codes to search two Indian Health Service (IHS) patient registration databases over the years 1998-2000, searching for individuals 19 years of age or younger with specific ICD-9-specified diagnoses. Crude estimates for disease prevalence were made based on the number of individuals identified with these diagnoses within the database.
Rheumatoid arthritis (RA) / juvenile rheumatoid arthritis (JRA) was the most frequent diagnosis given. The prevalence rate for JRA in the Oklahoma City Area was estimated as 53 per 100,000 individuals at risk, while in the Billings Area, the estimated prevalence was nearly twice that, at 115 per 100,000. These rates are considerably higher than those reported in the most recent European studies.
Chronic arthritis in childhood represents an important, though unrecognized, chronic health challenge within the American Indian population living in the United States.
We are beginning to understand the clinical nature of JAS, its relationship with other SSA, and factors involved in its pathogenesis. Clinical data may now allow early recognition of JAS through the identification of children with the SEA syndrome or chronic arthritis associated with the HLA-B27. Comparative clinical studies of the prevalence of the disease and the role of irnmunogenetic, racial and environmental factors are needed. It may be necessary to review current criteria for the diagnosis of JRA and to develop similar criteria for the diagnosis of AS in childhood and adolescence.
Study of products of genes present on a region on chromosome 6 known as the Major Histocompatibility Complex (MHC) is providing new insight into many chronic diseases of undetermined aetiology, including rheumatic diseases such as ankylosing spondylitis1,2 and rheumatoid arthritis3,4. The human MHC is called HLA, and it contains a tightly linked cluster of genes that encode for cell surface glycoprotein molecules expressed on the cell membrane of virtually all cells5–7. These molecules are involved in cell-to-cell interaction and have been subdivided into two distinct groups called class I and class II molecules6–8. The class I molecules are encoded by the HLA-A, -B, and -C loci of the MHC. These molecules display an exceptional degree of genetic polymorphism and are composed of an MHC-encoded heavy — or α — chain that is non-covalently bound to β2-microglobulin, a smaller and invariant polypeptide chain encoded by a gene located on another chromosome5–8. The class II molecules consist of two glycoprotein chains as well, the larger of the two chains is called α chain and the smaller one is called β chain. These two chains are closer in size than those of the class I molecules. Moreover, both α and β chains are encoded by genes located in the HLA-D region7,8.
Several studies of DNA restriction fragment length polymorphism (RFLP) in ankylosing spondylitis (AS) have been carried out.
The association between a recently identified class I HLA 9.2kb PvuII RFLP and AS remain controversial. In order to evaluate
this possible association in an Euro-Caucasian population, the genomic DNA of 42 AS patients and 18 patients with Reiter's
syndrome (RS) and 42 healthy controls was analysed. Non-association between 9.2kb PvuII RFLP and AS or RS was observed. As
described previously, a strong association between this fragment and HLA-A3 andlor HLA-A9 antigens was demonstrated. A study
of two families showed that this RFLP segregates with HLA-A3 and/or HLA-A9 and indepen dently of the HLA-B27. Our findings
support the view that the 9.2kb PvuII fragment is not universally associated with AS.
The association of HLA-B27 with ankylosing spondylitis and related spondyloarthropathies has been known for two decades and has provided a great impetus to the epidemiologic studies and also helped broaden the clinical spectrum of these diseases. The etiology of these diseases is likely to be multifactorial and include genetic, immunologic, and environmental mechanisms. The detailed three-dimensional x-ray crystallographic structure of B27 has now been reported. It has revealed electron density compatible with oligopeptides that are nine amino acid-long (nonamers) bound in the antigen-binding cleft of the molecule. Microsequence analysis of 11 peptides eluted from the antigen-binding cleft has confirmed that all are nonamers. The most restricted position in the bound peptide is the second position, where all the 11 peptides contain arginine. The side chain of arginine extends into the B pocket ("45 pocket"), which seems to act as a specificity side pocket in the antigen-binding cleft of the B27 molecule. It is very likely that an understanding of the detailed structure of B27, including the peptide-binding motif and the structural domains recognized by cytotoxic T cells, along with the recent development of the B27 transgenic rat model for spondyloarthropathies, will further enhance our understanding of the immunogenetics of these diseases. It is hoped that this will lead to the source of the arthritogenic triggers and possibly disease prevention by antigen-specific immunomodulation. Because T-cell activation is initiated by the formation of antigen-MHC complexes that are the ligands that are recognized by the antigen-specific T-cell receptor (TCR), it might be possible to inhibit this activation by blocking the antigen-binding cleft of MHC molecules by using high-affinity MHC-binding peptides (MHC blockade) or by a novel, new, and more efficient method of TCR antagonism.
Reiter's syndrome is very frequent in the Inuit of Greenland, because of high frequencies of venereal disease and HLA-B27. The authors report the results of the epidemiologic work and of the study of the effects of antibiotic treatment of venereal infection. In Reiter's syndrome patients, treatment of venereal infections by erythromycin or tetracycline was associated with a significant reduction in the rate of postvenereal arthritic flares.
Ankylosing spondylitis and related spondyloarthropathies show a remarkable association with a genetic marker--HLA-B27--and also illustrate the relationship between host and environmental factors. HLA-B27 has revitalized the epidemiology of spondyloarthropathies and has helped to broaden the clinical spectrum of these diseases. These and other aspects of descriptive and genetic epidemiology are reviewed.
We examined the distribution of non-B27 alleles of the HLA-B locus among B27+ patients with ankylosing spondylitis (AS), to detect any additional HLA-B locus allele(s) that may act in conjunction with B27 to increase susceptibility to AS. HLA-Bw60 (or B40 when the Bw60,61 split of B40 was not typed for) was shown to be increased among B27+ AS patients in each of 5 independent data sets. This increase was statistically significant in 4 of the 5 data sets studied, and the overall significance was P less than 0.00001. Susceptibility to AS in B27+ individuals was further increased by a factor of approximately 3 when Bw60 was also present. The distribution of HLA-A alleles on the B27-bearing haplotypes in AS patients was not significantly different from that in normal controls. On the other hand, the distribution of HLA-A alleles on Bw60-bearing haplotypes was significantly different from the distribution of A alleles on Bw60 haplotypes in the general population (P less than 0.0005). Bw60 was not increased in B27- patients with AS. A dominant mode of inheritance generally fits AS; however, our sib pair analysis indicates that the B27,Bw60 disease subgroup follows a more recessive mode of inheritance.
Recombinant DNA techniques appear to be a promising approach for identifying the genes responsible for influencing susceptibility to rheumatic disorders. The association of class I and class II RFLPs with AS and RA, respectively, provides further evidence that genes within the MHC play an important role in the etiology of these diseases. With regard to AS, the evidence gained by this approach suggests that a gene(s) in addition to B27 influences susceptibility to the disease. Furthermore, an RFLP has been identified that appears to distinguish clinical subtypes of the disease.
Subsequently, one would now like to clone disease-associated RFLPs and determine their DNA sequence. Comparison of their sequence with the sequences of other MHC genes should reveal the identity of the gene contained within the fragment. Next, the clones can be restriction mapped and subclones obtained that could be used as probes in case-control studies to determine if they are more strongly associated with the respective diseases than the original probes. It can also be informative to construct genomic libraries of patients with AS and RA, respectively. These libraries can be screened with the original probe used to detect the RFLP as well as the subclones of the RFLP fragments to obtain additional clones that again could be used as probes in case-control studies to identify RFLPs more strongly associated with the respective disease. By obtaining a series of overlapping clones in this manner, one could “walk” up and down the short arm of chromosome 6 searching for clones highly associated with the given disease. Those clones found to identify an RFLP highly associated with the disease could then be used as probes to determine whether the RFLP segregates with the disease in families with multiply-affected members. Identification of an RFLP that is strongly associated with the disease in case-control studies as well as concordant with the disease in family studies would provide presumptive evidence of a gene that plays a role in the etiology of the disease being studied.
At this step, however, one could not be certain that the actual susceptibility gene had been identified as opposed to a tightly linked gene. Sequencing of clones containing the disease-specific RFLP would be needed to compare with known sequences of other genes. It should be noted that the chromosome “walking” approach has proven effective in allowing investigators to clone the gene for retinoblastoma.³⁰ Unfortunately, with multifactoral disorders such as the rheumatic diseases, it may be difficult to identify the actual gene(s). However, it is reasonable to speculate that at least one of the genes will be involved in some aspect of the immune response. This could be tested using transgenic mice or by investigating cells in culture transfected with the gene.
The development of a probe that will identify an RFLP strongly associated with AS or RA is clearly a desirable goal. These genetic markers could more accurately predict risk for the occurrence of disease and, it is hoped, response to therapy and outcome.
Ninety percent of individuals with ankylosing spondylitis (AS) express HLA-B27. To determine if HLA-B27 coding sequences from normal vs AS individuals show differences that might relate to the etiology of the disease, the gene coding for this allele was cloned from three different partial genomic libraries. These libraries were made with DNA from three different cell lines expressing HLA-B27: MRWC (HLA-B27, 14), obtained from an AS patient; KCA (HLA-B27, w44), obtained from a known normal individual; and MVL (HLA-B27, 27), a homozygous consanguineous cell line of unknown origin. To increase the number of clones coding for the HLA-B locus, partial libraries were made using a complete Eco RI digestion of genomic DNA in the lambda vector 607. The libraries were screened with two probes; one probe hybridizes to all HLA-A, B, C class I genes, and the other to a small subpopulation of class I genes, including the B locus. DNA from clones hybridizing with both probes was transfected into murine L cells. Cell surface expression of HLA-B27 on murine L cells was detected with a polymorphic monoclonal antibody (ME1) specific for HLA-B27, 7, 22. DNA from those clones positive for HLA-B27 by transfection was subcloned into the Xba I site of M13mp18 and the DNA sequence for exons 2 through 4 (encoding domains alpha 1, alpha 2, and alpha 3) was determined by the dideoxy technique by using synthetic oligonucleotide primers or the M13 primer. The resulting sequences show no difference between HLA-B27 alpha 1, alpha 2, alpha 3 domains from a known AS patient and a known normal individual.
The term spondyloarthropathy, currently used to describe some forms of idiopathic arthritis of childhood, may be inappropriate because most children included in this category do not have arthritis of the spine, and inflammatory disease of the sacroiliac joints is an infrequent or late finding. Juvenile AS, the archetype, or "complete" disease may account for only one fifth of the so-called "spondyloarthropathies". "Incomplete" or "early" spondyloarthropathies are most frequent. Such children may not develop axial symptoms and signs for 5 to 10 years after onset, and they may be better characterized as having enthesitis-related arthritis, a term proposed by a recent task force of the International League Against Rheumatism (ILAR). Reactive arthritis, although etiologically linked with the spondyloarthropathies, uncommonly progresses to AS in childhood; most patients have peripheral arthritis with or without enthesitis resolving in the relatively short term. The arthritis associated with IBD is more commonly peripheral than axial. Although axial disease undoubtedly occurs in JPsA, in the authors' experience it is very uncommon.
To study the association between the occurrence of peripheral arthritis and of acute anterior uveitis during the course of ankylosing spondylitis (AS).
Retrospective clinical follow up by both chart review and direct patient interview was performed on 271 individuals comprised of 222 local white and 49 Taiwanese individuals with AS.
Of 89 white patients with acute anterior uveitis, 36 (40.4%) also had peripheral arthritis, compared with only 33 (24.8%) having peripheral arthritis among the 133 who did not have acute anterior uveitis (p < 0.02). Thirty seven (78.7%) of 49 Taiwanese individuals with AS had peripheral arthritis and these included all 10 patients with acute anterior uveitis from the entire disease cohort (p < 0.05).
This cross-sectional survey of AS patients supports the view that patients who develop peripheral arthritis are also more likely to develop acute anterior uveitis.
To provide a single source for the best available estimates of the national prevalence of arthritis in general and of selected musculoskeletal disorders (osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, the spondylarthropathies, systemic lupus erythematosus, scleroderma, polymyalgia rheumatica/giant cell arteritis, gout, fibromyalgia, and low back pain).
The National Arthritis Data Workgroup reviewed data from available surveys, such as the National Health and Nutrition Examination Survey series. For overall national estimates, we used surveys based on representative samples. Because data based on national population samples are unavailable for most specific musculoskeletal conditions, we derived data from various smaller survey samples from defined populations. Prevalence estimates from these surveys were linked to 1990 US Bureau of the Census population data to calculate national estimates. We also estimated the expected frequency of arthritis in the year 2020.
Current national estimates are provided, with important caveats regarding their interpretation, for self-reported arthritis and selected conditions. An estimated 15% (40 million) of Americans had some form of arthritis in 1995. By the year 2020, an estimated 18.2% (59.4 million) will be affected.
Given the limitations of the data on which they are based, this report provides the best available prevalence estimates for arthritis and other rheumatic conditions overall, and for selected musculoskeletal disorders, in the US population.