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Diagnostic Value of HLA-B27 Testing in Ankylosing Spondylitis and Reiter's Syndrome
Abstract
Typing for histocompatibility antigen (HLA)-B27 has been suggested as a clinically valuable diagnostic test for ankylosing spondylitis and Reiter's syndrome, although some decry its use for this purpose. Diagnoses can be made in most patients with these diseases on the basis of the history, physical examination, and roentgenographic findings. The B27 test cannot be used to screen an asymptomatic population to detect these diseases and should not be thought of as a routine diagnostic test. We present probability graphs derived from Bayes' theorem, which show that for certain patients the B27 test, when used properly, is of clinical value as an aid to diagnosis. Proper application of the B27 test in clinical medicine is discussed. The test result does not absolutely confirm or exclude the presence of these diseases; it merely provides a probability statement on their existence in the patient. The test is therefore most useful to physicians who understand the use of probability reasoning in clinical decision making.
... 47 However, an expert review some years later in 1980 concluded 'that knowledge of the patient's HLA-B27 status seems to provide only minimal help to the physician'. 48 A more sophisticated review in 1982 49 confirmed that a diagnosis of AS can, in most patients, be made on the basis of the history, physical examination and roentgenographic findings and that HLA-B27 should not be used as a routine diagnostic test. It was also made clear that B27 testing cannot be used to screen an asymptomatic population to detect the disease, and it was recommended not to use it as a routine diagnostic test. ...
... Thus, it was concluded that the test is useful to physicians who understand probability reasoning in clinical decision making. 49 This statement is still valid 40 years later. ...
... 79 However, HLA B27 alone is never sufficient to establish the diagnosis. 49 A German population-based study (SHIP) showed a high frequency of inflammation in the axial skeleton in normal individuals with HLA B27 and, in women, a history of delivery as significant risk factors. 80 Of interest, the impact of HLA B27 was only significant in male individuals. ...
The human lymphocyte antigen B27 (HLA B27) is a member of the HLA class I family of genes in the major histocompatibility complex whose name goes back to its discovery in studies of transplanted tissue compatibility. Its prevalence in the mid-European population is about 8%. The association of HLA B27 alleles with ankylosing spondylitis (AS), a highly heritable disease, which is part of the spectrum of axial spondyloarthritis (axSpA), was discovered 50 years ago. HLA B27 explains less than 30% of the total genetic load. About 60%–90% of axSpA patients worldwide carry HLA B27. The prevalence of the disease is linked to the frequency of HLA B27 in the population which implies that there are relevant differences. Among the roughly 200 subtypes known there are two which are not disease associated. The function of HLA class I molecules is to present peptides to the immune system to defend the organism against microbes targeted by CD8+T cells. This is much supported by the role of the endoplasmic reticulum aminopeptidase 1 (ERAP 1) in AS, an enzyme that is responsible for the intracellular trimming of peptides, since polymorphisms of this gene are only associated with HLA-B27+ disease. The arthritogenic peptide hypothesis trying to explain the pathogenesis of AS is based on that very immune function assuming that also self peptides can be presented. HLA-B27 also plays an important role in classification, diagnosis and severitiy of axSpA.
... The strong genetic association between axSpA and HLA-B27 has, in the meantime, been extended to other genes/alleles such as ERAP-1 and the IL-23R [20,21], but their exact pathogenetic role has not yet been clarified. Even though this lab test was clearly shown to be helpful to diagnose axSpA by A.Khan [22], it didn't become part of AS classification criteria in 1984 [6] and the ESSG criteria in 1991 [23] but it was included in the Amor criteria from 1990 [24] and the ASAS criteria in 2009 [25]. However, more than 95% of HLA-B27 carriers will never get the disease, and HLA-B27 carriage in the European-ancestry general population was shown not to influence survival [26]. ...
... The first systematic evaluation of the value of HLA B27 testing to diagnose AS was published by A.Khan in 1982 [22]. It took several decades until its value became clearer [30] and again some years until it became part of the actual classification criteria [25]. ...
Purpose of Review
Axial spondyloarthritis (axSpA) is a rather prevalent chronic inflammatory rheumatic disease that affects already relatively young patients. It has been known better since the end of the nineteenth century but quite a lot has been learned since the early 60ies when the first classification (diagnostic) criteria for ankylosing spondylitis (AS) were agreed on. I have been part of many developments in the last 30 years, and I’m happy to have been able to contribute to the scientific progress in terms of diagnosis, imaging, pathophysiology and therapy. When I was asked to write a manuscript about the SpA concept I felt honored. Thus, the purpose of this extensive review was, on the one hand, to describe the history of AS and axSpA, and on the other hand, to reason about the concept and the gestalt of axSpA, and finally to deliver some ideas what future researchers could possibly do to further study the disease.
Recent Findings
The last 3 decades were full of innovations for both, classification and treatment of axSpA which also helped us to learn about the pathophysiology. Thus, TNFa, IL-17, IL-23 and Janus kinase are established targets to reduce inflammation. IL-17 and IL-23 are very special in that regard because they both work for psoriasis but only anti-IL-17 agents which don’t work in IBD are approved for axSpA, while IL 23 inhibitors are approved for both, psoriasis and IBD, but they don’t work in axSpA. New imaging techniques such as low dose CT and synthetic MRI are likely to improve the detection of both active and structural lesions of axSpA.
Summary
This manuscript tries to describe the most important findings about axSpA. The main aim of research remains to discover the pathophysiology and to further improve treatment options in order to reduce and abolish inflammation and prevent new bone formation to increase the quality of life of our patients. The differences between male and female disease and the role of the immune system in axSpA are now the main challenges, and the role of special T-cell receptors seem to deserve special interest.
... Pathogens commonly associated with Reiter's syndrome are Shigella, Salmonella, Yersinia, Campylobacter, Amoeba and Chlamydia. 1 The estimated incidence of Reiter's syndrome is approximately 4/1000 per year. 8 The genetic predisposition to Reiter's syndrome is well established. Eighty percent of patients are positive to HLA-B27 compared to 6% of normal occasions 1,7 . ...
... Other manifestations may include fever, prodromal symptoms, rheumatology lesions, and gastrointestinal and cardiac involvement 10 . Reiter's syndrome could be incomplete when there is no evidence of enteric or urethral inflammation 8 . Clinical assessment was done by taking full history and doing careful physical examination. ...
Objective: To study the epidemiological and clinical features of Reiter's syndrome in patients who visited the rheumatology clinic in King Hussein Medical Centre (KHMC), Jordan. Methods: A prospective study, including 43 patients with the diagnosis of Reiter's syndrome was done. Patients were assessed by taking complete history, physical examination and appropriate investigations including urinalysis and culture, stool examination and culture, synovial fluid analysis, complement fixation test for chlamydia trachomatis, complete blood count, erythrocyte sedimentation rate, rheumatoid factor, antinuclear antibodies, HLA-B27 and radiological study. Results: All patients in this study were white men, with mean age of 26.3 years. HLA-B27 was positive in 37 patients (86%). Most cases were post venereal (32 patients, 74%) while the rest were dysenteric. The clinical manifestations were arthritis in all patients (100%), urethritis in 21 patients (48%), ocular involvement in 20 patients (46%), diarrhoea in 12 patients (28%), painless oral ulcers in 11 patients (26%), skin lesions in 5 patients (12%) and constitutional symptoms in 7 patients (16%). Arthritis was mostly oligoarticular (25 patients, 58%) with asymmetrical pattern in 34 patients (78%). Large joints of lower extremity were most involved (29 patients, 68%). Rheumatoid factor and antinuclear antibodies were negative in all patients. Relapses occurred in 7 patients (16%) after a mean period of 6.2 months. Conclusion: It is concluded that the epidemiological and clinical features of Reiter's syndrome in Jordan are not different from those in the literature.
... Thus, while it is not a good test for the screening of AS in community or population due to low post-test probability (false positivity among those without clinical features of inflammatory back pain), it is a highly useful test among those with clinical features of inflammatory back pain (having high pre-test probability). 3,4 Over the years rheumatologists have evolved clinical instruments for recognizing inflammatory back pain including Calin, Berlin criteria, Assessment of Ankylosing Spondylitis (ASAS) group and the most recent Weisman criteria [discussed in refs 1, 2], and have become proficient in its recognition. Therefore, low back pain patients evaluated by rheumatologists automatically fall in the high-pre-test probability group, thus making HLA-B27 test a highly sensitive and specific diagnostic test. ...
... Realizing the importance of HLA-B27 in the diagnosis of AS, the ASAS group has recommended its use in the algorithmic approach for diagnosing these conditions. 1 The role of HLA-B27 in the diagnosis of this group of conditions has been discussed extensively elsewhere. 3,4 Under these circumstances, the reliability of the results for HLA-B27 gene screen becomes crucial. ...
... The main reason for the absence of Carol Nachman Prize winners in the field of spondyloarthritis before 1992 mainly indicates that the focus of international and national rheumatology was rather on rheumatoid arthritis and connective tissue diseases. The discovery of the HLA-B27 association by D. Brewerton [114], the proposed concept of spondyloarthritis by J. Moll & V. Wright [115], the first description of inflammatory back pain by A. Calin [116], the first hint that NSAIDs may inhibit radiographic progression in AS [117], the detailed radiographic concept of radiographic changes in the sacroiliac joint by W. Dihlmann [118], the distinguished and still valid calculation of the diagnostic performance of HLA-B27 by M. Khan [119], and the publication of the modified New York criteria for AS by S. van der Linden [120] are good examples of valuable scientific research in the field of AS. ...
The city and casino of Wiesbaden, capital of the German state Hessen, have endowed the Carol Nachman Prize to promote research work in the field of rheumatology since 1972. The prize, endowed with 37,500 €, is the second highest medical award in Germany and serves to promote clinical, therapeutic, and experimental research work in the field of rheumatology. In June 2022, the 50-year anniversary was celebrated. In the symposium preceding the award ceremony, an overview was given on the significance of spondyloarthritis for the work of the awardees in the past 30 years. This overview has now been put together to inform the interested community of the work performed, including the opinion of the awardees regarding what they consider to be their most important contribution.
... Diagnosing AS in most patients often relies on a combination of clinical evaluation and imaging, although an unnecessary delay of several years is sometimes encountered, more so among women. The presence of HLA-B*27, in an appropriate clinical context, can enhance clinical suspicion for difficult-to-diagnose cases, such as early or atypical presentations, juvenile onset, or undifferentiated forms of SpA [93]. However, it is important to note that HLA-B*27 is not a definitive confirmation of the disease and cannot serve as a standalone screening test. ...
Purpose of Review
To commemorate the 50th anniversary of the groundbreaking discovery of a remarkably strong association between HLA-B*27 and ankylosing spondylitis (AS).
Recent Findings
In addition to HLA-B*27, more than 116 other recognized genetic risk variants have been identified, while epigenetic factors largely remain unexplored in this context. Among patients with AS who carry the HLA-B*27 gene, clonally expanded CD8 + T cells can be found in their bloodstream and within inflamed tissues. Moreover, the α and β chain motifs of these T-cell receptors demonstrate a distinct affinity for certain self- and microbial-derived peptides, leading to an autoimmune response that ultimately results in the onset of the disease. These distinctive peptide-binding and presentation characteristics are a hallmark of the disease-associated HLA-B*27:05 subtype but are absent in HLA-B*27:09, a subtype not associated with the disease, differing by only a single amino acid. This discovery represents a significant advancement in unraveling the 50-year-old puzzle of how HLA-B*27 contributes to the development of AS.
Summary
These findings will significantly accelerate the process of identifying peptides, both self- and microbial-derived, that instigate autoimmunity. This, in return, will pave the way for the development of more accurate and effective targeted treatments. Moreover, the discovery of improved biomarkers, in conjunction with the emerging technology of electric field molecular fingerprinting, has the potential to greatly bolster early diagnosis capabilities. A very recently published groundbreak paper underscores the remarkable effectiveness of targeting and eliminating disease-causing T cells in a HLA-B*27 patients with AS. This pivotal advancement not only signifies a paradigm shift but also bolsters the potential for preventing the disease in individuals carrying high-risk genetic variants.
... HLA-B27 is strongly associated with axSpA and can aid in its diagnosis in clinical practice, but its absence can wrongly delay the diagnosis [10]. Therefore, the clinical utility of the presence or absence of HLA-B27 in a patient should be interpreted in light of a prior clinical likelihood estimated on the presence of other spondyloarthritis features. ...
Purpose of Review
This article aims to review the challenges in axial spondyloarthritis diagnosis and identify the possible contributing factors.
Recent Findings
The inability to reach an accurate diagnosis in a timely fashion can lead to treatment delays and worse disease outcomes. The lack of validated diagnostic criteria and the misuse of the currently available classification criteria could be contributing. There is also significant inter-reader variability in interpreting images, and the radiologic definitions of axial spondyloarthritis continue to be re-defined to improve their positive predictive value. The role of inflammatory back pain features, serologic biomarkers, genetics, and their diagnostic contribution to axial spondyloarthritis continues to be investigated.
Summary
There is still a significant amount of delay in the diagnosis of axial spondyloarthritis. Appreciating the factors that contribute to this delay is of utmost importance to close the gap. It is similarly important to recognize other conditions that may present with symptoms that mimic axial spondyloarthritis so that misdiagnosis and wrong treatment can be avoided.
... [12] Sclerosis and obliteration of the joint space, ligamentous calcification, squaring of the vertebrae, and in end stage disease, the characteristic ankylosed "bamboo" spine can be seen on plain radiography. It is noteworthy that seropositivity is neither necessary nor sufficient for establishing the diagnosis of AS. [13] Establishing the diagnosis of AS relies on a thorough history and physical examination besides radiologic confirmation. The disease should not be ruled out if the aforementioned criteria are not met. ...
The seronegative spondyloarthropathies are a group of autoimmune inflammatory diseases lacking rheumatoid factor or antinuclear antibody in their serum. They include ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis, spondylitis associated with Crohn’s disease and ulcerative colitis, and undifferentiated spondyloarthropathies. Inflammation mostly affects the axial joints, entheses, and extra-articular structures such as uveal tract, gastrointestinal tract, mucocutaneous tissue, and heart. Uveitis is the most common extra-articular manifestation. Spondyloarthropathies, especially AS, have a strong association with the presence of Human Leukocyte Antigen (HLA)-B27 gene. AS happens earlier in HLA-B27 patients and men are more prone to the disease. Uveitis, typically unilateral nongranulomatous acute anterior uveitis, occurs in up to 50% of the patients with AS. HLA-B27 positivity correlates with more frequent flare-ups. Conjunctivitis and scleritis are rare ocular manifestations of AS. To establish the diagnosis of AS, at least one clinical and one radiologic parameter are required for definitive diagnosis. Magnetic resonance imaging (MRI) or bone scan can help early detection of the axial skeleton inflammation. The course of eye and joint involvement are not correlated. Short-term treatment with topical corticosteroids and cycloplegic agents control the uveitis attack. In resistant cases, local or systemic therapy with corticosteroids are recommended. NSAIDs, disease-modifying anti-rheumatic drugs (DMARDs), methotrexate, azathioprine, anti-IL-17A monoclonal antibodies, and TNF- α antagonists are effective treatments for ocular and systemic manifestations of AS. If not treated adequately, uveitis may become recalcitrant and extend posteriorly. Functional impairment due to joint destruction can also occur as a result of undertreatment.
... The results of the present study reiterate results of other studies that HLA-B27 alone is not a useful screening tool for axial SpA (37,38). Although a positive test in an "at-risk" patient can be highly predictive of a diagnosis of axial SpA, the prevalence of ankylosing spondylitis in persons who are HLA-B27 positive is only 1-6% (39). ...
Objective
To evaluate a stratified screening process for the early identification of axial spondyloarthritis (SpA) with consideration of the following: 1) wait times from primary care to rheumatology screen, 2) incremental precision and accuracy from primary care to rheumatology screening, and 3) diagnostic delay.
Methods
Adults with low back pain attending primary care at low back pain clinics prospectively underwent a primary standardized clinical screening. Patients with low back pain of >3 months who experienced symptom onset at age <50 years were referred for a comprehensive secondary screening by a physical therapist with advanced rheumatology training. At secondary screening, patients with features of inflammation were classified as being at a low, medium, or high risk for axial SpA versus no risk for axial SpA. Precision and accuracy of this screening strata were measured against a rheumatologist with expertise in axial SpA.
Results
Overall, 405 patients underwent primary and secondary screening in the present study. The study cohort had a mean ± SD age of 36.9 ± 9.9 years, and 55% were women. HLA–B27 was present in 14.4% of patients. Median wait time from primary screening to secondary screening was 15 days. Axial SpA risk assignment by rheumatologist was 64.9% for no risk or low risk for axial SpA and 35.1% for medium risk or high risk for axial SpA. The best combination of sensitivity (68%), specificity (90%), positive predictive values (80%), and negative predictive values (84%) was evident in the secondary screening. In this cohort, 15.6% of patients received a final diagnosis of axial SpA. Median low back pain duration from symptom onset to diagnosis was 2 years for nonradiographic axial SpA and 7 years for ankylosing spondylitis.
Conclusion
A stratified interprofessional screening process can facilitate rapid diagnosis of persistent low back pain with high precision and accuracy in patients who have axial SpA.
... HLA-B*27 typing has been proposed as a useful test for AS and related spondyloarthropathies (SpA), and thus the availability of a reliable and accurate detection method is important (3). Although the result of HLA-B*27 typing is unable confirm or exclude the diagnosis of this disease (10), different subtypes may be associated with different ethnic groups, clinical manifestation, age of onset and prognosis (11). ...
The association of spondyloarthropathies with different alleles of human leukocyte antigen (HLA) B*27 is well established. Different subtypes of HLA-B*27 may be linked with different ethnic groups, distinct clinical manifestations, specific age of onset and different prognoses. Polymerase chain reaction with sequence specific primers (PCR-SSP) is the most frequently adapted molecular method used for the recognition of HLA-B*27-specific DNA sequences. The aim of the present study was to standarise an in-house protocol of PCR-SSP for HLA-B*27 allele detection for use in the Armed Forces Institute of Pathology (AFIP), Pakistan, with consideration of its cost effectiveness. A total of 49 individual samples were included, comprising 10 transplant samples determined to be HLA-B*27-negative by PCR-SSP and 39 HLA-B*27-positive samples determined by flow cytometry, obtained from patients who were symptomatic and referred for HLA-B*27 testing. By altering each variable individually, an in-house PCR-SSP protocol was optimized to amplify common HLA-B*27 alleles (2701-2721, 2723-2730). To discriminate B*27 from all other HLA-B alleles, a low-resolution HLA-B typing set with a 96 PCR-SSP primer mixture was used in conjunction. Among the 39 HLA-B*27-positive specimens, 31 (79%) were detected as positive by PCR-SSP, with the remaining samples failing due to a sub-optimized protocol and/or low DNA concentration. Additionally, there was complete concordance between flow cytometry and in-house PCR, and the sensitivity and specificity of the PCR-SSP were determined to be 100%. In conclusion, in-house SSP-PCR is, standard method for the detection of HLA-B*27 alleles. The determination of associations between specific HLA-B*27 alleles and AS may aid to identify individuals at higher risk of developing the disease. Furthermore, the identification of individuals at risk may aid to adapt preventive strategies.
... Other common alleles reported from India are HLA-B*27:07, HLA-B*27:02, and HLA-B*27:10, all of which have been documented to be associated with AS. [7][8][9][10][11][12] Serological techniques such as microcytotoxicity and flow cytometry for testing HLA-B27 require viable cells that adequately express HLA-B27 and may give false negative results if HLA-B27 is downregulated or "masked". 13 Flow cytometry, a widely used technique in India, is rapid, high-throughput and relatively inexpensive but has been reported to lack specificity, especially in the presence of antigens that cross-react with HLA-B27, such as HLA-B7 and HLA-B37. ...
Background:
Determination of HLA-B27 status plays an important role as adjuvant in suspected cases for diagnosis of Ankylosing Spondilytis (AS). Objectives of this study were to evaluate (i) flow cytometry method in comparison with DNA microarray for HLA-B27 typing and (ii) EUROArray HLA-B27 Direct assay for HLA-B27 allele detection along with discrimination of AS/non-AS subtypes in Indian population.
Methods:
A total of 7543 patients with a presumptive clinical diagnosis of AS were referred for screening of HLA-B27. All samples were initially tested by flow cytometry, and based on its findings, 1560 samples were analyzed for the presence of HLA-B27 allele by microarray technology. A subset of samples (n = 200) were further tested by DNA sequencing for identification of HLA-B27 subtypes.
Results:
Screening of HLA-B27 by flow cytometry reported 1551 positive (20.56%) and 5556 negative (73.65%) cases. Remaining 436 (5.78%) samples were identified within equivocal zone. Of cases (n = 1560) analyzed by microarray method, 1333 (85.44%) and 227 (14.55%) were detected microarray positive and negative, respectively. DNA sequencing identified HLA-B*27:07 as the predominant subtype among cases showing ex2 positivity by microarray method. Of 200 cases, 20 cases (14 of HLA-B*07 and 6 of HLA-B*37) of HLA-B27 cross-reactive subtypes were also identified.
Conclusion:
We recommend DNA typing as a complementary tool along with flow cytometry to accomplish successful HLA-B27 phenotype determination. This is the first study among Indian population to evaluate efficacy of EUROArray to detect B27 allele and its potential to indicate the presence of nondisease-associated alleles in Indian population.
... Beginning with a clinical estimate of the likelihood of ankylosing spondylitis or a related spondarthropathy, Bayes' theorem can be used to calculate the probability that a patient has the disease, depending on whether they transpire to be HLA-B27 positive or negative. 41 The usefulness of a positive result will be greatest in populations, such as the Japanese, that have a low general prevalence of HLA-B27 and yet its association with ankylosing spondylitis is strong. For the other spondarthritides, which are less strongly linked with HLA-B27, diagnosis is based primarily on the associated clinical features. ...
... The diagnostic utility of HLA-B27 testing depends on the clinician's pre-test estimate (clinical presentation, clinical judgement and experience). The higher the pre-test probability, the higher the post-test probability of reaching a diagnostic threshold and this utility is less pronounced at the extremes of diagnostic probability testing (if pretest probability is closer to 0 or 100%) [92]. It has been calculated that for a positive HLA-B27 test to provide an acceptable post-test probability of 95%, the physician must be > 50% certain of the diagnosis before the test is performed [90]. ...
The association between HLA-B27 and AS was first established in the early 1970s. Since then, our understanding of this disease has changed, such that we now recognize AS to be the extreme of the clinical phenotype within a disease spectrum known as axial SpA (axSpA). Recent advances in therapeutic options have driven the need for earlier diagnosis and many screening strategies have been proposed to facilitate this. In parallel, our understanding of axSpA genetics, and especially the contribution of HLA-B27, has expanded. In this article we will present and discuss the evidence supporting the use of HLA-B27 in clinical practice. We will briefly summarize the evolution of the concept of axSpA, the prevalence of HLA-B27 and axSpA and the potential role of HLA-B27 in the aetiopathogenesis of axSpA and focus on the utility of HLA-B27 in everyday clinical practice.
... This assessment has no additional value in established disease or as a pure screening tool. [4] However in young patients with inflammatory chronic back pain, a positive HLA-B27 test increases the likelihood of having AS particularly if imaging of the sacroiliac joints does not provide conclusive results. A normal erythrocyte sedimentation rate (ESR) or normal C-reactive protein level does not exclude active disease. ...
... 44 This is similar to recommendations made for B27 testing in the spondyloarthropathies. 55 Testing is best directed by a careful and thorough patient history and physical exam and the identification of certain key clinical features should direct testing for HLA-B27. ...
Acute anterior uveitis is generally recognized as the most common form of uveitis. An association with HLA-B27 is seen in approximately half of cases of acute anterior uveitis. The prevalence of HLA-B27 varies widely between ethnic populations, with an approximate 8-10% prevalence in non-Hispanic whites and lower prevalence in Mexican- (4%) and African- (2-4%) Americans. A group of systemic inflammatory diseases, the spondyloarthropathies, similarly demonstrates a strong association with HLA-B27. The strength of association varies, depending on the specific spondyloarthropathy, with the strongest association found in patients with ankylosing spondylitis. The majority of patients with HLA-B27 associated uveitis will have an underlying spondyloarthropathy. Suspicion for HLA-B27 associated uveitis should prompt a careful clinical history to assess for features of a spondyloarthropathy as the characteristics of any associated uveitis may vary.
... The difference between groups regarding HLA-B27 status was to be expected, because frequencies of HLA-B27 vary sharply among the various forms of SpA and among different ethnic groups 5,30 . For example, in healthy individuals, the frequency of HLA-B27 in American blacks ranges from 2% to 4%; in Mexican mestizos it varies between 2% and 5% 31,32 ; in Colombia the percentage is under 1% 33 ; and in whites it is 8%. ...
... VOL. 12 No. 3 -2005 radiológicos, sin necesidad de ordenar una prueba de HLA B27 5,129,130 . ...
Resumen Las espondiloartropatías son un grupo de enfer-medades inflamatorias crónicas, de las cuales se des-tacan especialmente la espondilitis anquilosante, artritis reactiva, artritis psoriásica, artritis asocia-da con la enfermedad inflamatoria intestinal y las espondiloartropatías indiferenciadas. Los subgrupos más comunes de espondiloartropatías son la espondilitis anquilosante y la espondiloartropatía indiferenciada. El diagnóstico de la espondilitis anquilosante se basa especialmente en los hallazgos radiológicos inequívocos de sacroiliítis de grado 2 bilateralmente o grado 3 unilateralmente. Sin em-bargo en la fase temprana de la enfermedad, los es-tudios radiológicos no son lo suficientemente sensibles como para mostrar la presencia de sacroiliítis y por lo general pueden tardar varios años para detectar la presencia de sacroiliitis radiológica; de esta ma-nera el diagnóstico de espondilitis anquilosante pue-de tardar hasta 8 a 11 años luego del inicio de los síntomas; como consecuencia de ello, el diagnóstico de espondiloartropatía con compromiso axial en au-sencia de sacroiliítis radiológica es de gran dificul-tad para el reumatólogo. En los estadíos tempranos, el test de HLA B27 y la resonancia magnética de articulaciones sacroiliacas son útiles en el diagnósti-co temprano. En presencia de dolor crónico de es-palda la probabilidad de espondiloartropatía axial es de un 5% y aumenta a un 14% en presencia de dolor de espalda inflamatorio; la probabilidad de espondiloartropatía axial aumenta a un 90% en pre-sencia de = 3 hallazgos de espondiloartropatías (talagia, uveítis, dactilitis, historia familiar positiva, dolor glúteo alternante, psoriasis, enfermedad inflamatoria intestinal, artritis asimétrica, respues-ta favorable a los antiinflamatorios no esteroideos). De otra parte, la positividad del HLA B27 y la reso-nancia magnética aumentan la probabilidad de la en-fermedad, en especial en aquellos casos que no presentan otros hallazgos de espondiloartropatías o que presentan 1 a 2 manifestaciones de espondilo-artropatías. En pacientes con espondiloartropatía psoriásica o asociada con la enfermedad inflamatoria intestinal el uso del HLA B27 es de valor limitado, ya que estas entidades por lo general tienen una aso-ciación negativa con el HLA B27. También se debe tener en cuenta, que la utilidad del HLA B27 y sus diferentes subtipos difiere entre los diferentes gru-pos étnicos y su valor en el diagnóstico depende de la probabilidad pre-test individual de cada caso. Palabras Clave: espondiloartropatías seronega-tivas, espondilitis anquilosante, diagnostico temprano.
... Concerning the association SSAs with positive tests for HLA-B27, most people who have a positive test do not have these diseases, and some patients who do have one of the SSA diseases have negative tests for HLA-B27. Thus, this test cannot exclude or confirm these diseases [18]. But the patients with positive HLA-B27 have more severe and acute disease [19]. ...
Spine involvement is less common in Reiter's syndrome than in other seronegative spondyloarthropathies. Also, cervical spine involvement rarely occurs in Reiter's syndrome and other spondyloarthropathies. This paper reports a rare case of Reiter's syndrome in which there was cervical spine involvement that presented clinically as an atlanto-axial rotatory subluxation. Reiter's Syndrome (RS) is one of the most common types of seronegative spondyloarthropathies (SSAs) that presents clinically with a triad of symptoms, i.e., conjunctivitis, urethritis, and arthritis. This case highlighted the importance of radiographs of the lateral cervical spine and dynamic cervical imaging for all patients who have Reiter's syndrome with cervical spine symptoms to ensure that this dangerous abnormality is not overlooked.
... Finally we have no data on the frequency of HLA B-27 in our population or our patients. However, in most adult patients, AS can be diagnosed using clinical criteria without HLA-B27 information (35). Moreover, diagnostic criteria for AS are nearly the same, irrespective of information on HLA-B27 (7, 23). ...
To evaluate the incidence and prevalence of ankylosing spondylitis (AS) in southern Albania and to assess the association of various demographic risk factors with the severity of disease.
This is an observational study with cross-sectional analyses, conducted in the region of Gjirokaster, between 1995 until 2011. The diagnosis of AS was based on the modified New York criteria. Data on population are obtained from the reports of the National Institute of Statistics.
Between 1995 and 2011, there were 54 patients diagnosed with AS. Of them, 48 subjects were males (88.9%) and 6 subjects females (11.1%). The AS prevalence in adult population (≥14 years of age), in December 2010, was 0.061%. The 5-year incidence (2006-2010) in adult population was 0.006 %. The mean age at the onset of disease was 29.7±8.4 years. The mean age in 2011 (n=50 subjects) was 51.6±12.7 years. The duration of the disease was 22.7±11.2 years. More than two thirds of the patients (70.3%) were in the advanced radiological stages of the disease. A younger age at the onset of the disease, longer delay in diagnosis, lower educational level and smoking were significant independent factors associated with the advanced forms of the disease.
In southern Albania, the AS prevalence in 2010 was 0.061% and the 5-year incidence (2006-2010) was 6 new cases per 105 adults. The incidence and prevalence of AS in Southern Albania are close to the respective regional epidemiological data.
... Devido a isso, o teste para HLA-B27 deve ser considerado especialmente nos pacientes que apresentem dor infl amatória na coluna, pois esses pacientes apresentam maior probabilidade de defi nição de um diagnóstico. 32 A doença apresenta manifestações: 1) Sistêmicas A apresentação clássica tem início com dor infl amatória na coluna, de forma insidiosa, com rigidez matinal e melhora com exercício, piorando com repouso ou inatividade. Outras manifestações das espondiloartrites soronegativas incluem astenia, fadiga, emagrecimento leve, febrícula. ...
The present article reviews the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of ankylosing spondylitis and its association with ocular changes. The authors used the PubMed (MEDLINE), LILACS, and Ophthalmology Library databases. Ankylosing spondylitis is a chronic inflammatory disease that usually affects the axial skeleton and can progress to stiffness and progressive functional limitation. Ankylosing spondylitis usually begins around the second to third decade of life, preferentially in HLA-B27-positive white males. Its etiology and pathogenesis are not completely understood, and its diagnosis is diffi cult. Clinical control and treatment are frequently satisfactory. Acute anterior uveíte is the most common extra-articular manifestation, occurring in 20%-30% of the patients with ankylosing spondylitis. Approximately half of the acute anterior uveíte cases are associated with the presence of the HLA-B27 antigen. It can be the first manifestation of an undiagnosed rheumatic disease, usually having a good prognosis and appropriate response to treatment. In conclusion, for better assessment and treatment of patients with uveitis, ophthalmologists and rheumatologists should work together.
Axial spondyloarthritis (axSpA) is a frequent inflammatory rheumatic disease mainly affecting the axial skeleton causing inflammatory back pain. If chronic inflammation persists new bone formation may occur possibly leading to irreversible spinal stiffness. The disease has a strong genetic background with HLA-B27 as the major factor. For diagnostic purposes, imaging is of critical importance—especially conventional radiography and magnetic resonance imaging (MRI). While the former has advantages in the detection of bony changes such as the syndesmophytes, MRI is used to detect axial inflammation but also erosions in the sacroiliac joint. Treatment follows the treat-to-target strategy starting with non-steroidal anti-inflammatory drugs (NSAIDs) in the first line, and later, if high disease activity persists, therapy with biologic disease modifying anti-rheumatic drugs (bDMARDs) is according to international recommendations indicated. For the treatment of axSpA, important targets such as tumor necrosis factor alpha (TNFα) and interleukin (IL)-17 have been identified, and several of their inhibitors (i) including some biosimilars for the former have been approved. Recently, also inhibition of Janus kinases was shown to be efficacious. There is evidence that long term inhibition of inflammation with TNFi can reduce bone formation.
Zusammenfassung
Die axiale Spondyloarthritis (axSpA) ist eine entzündlich-rheumatische Erkrankung, die typischerweise durch entzündlichen Rückenschmerz (eRs) gekennzeichnet ist. Der Terminus axSpA hat den lange gebräulichen Begriff ankylosierende Spondylitis (AS) weitgehend abgelöst. Der eRs ist durch Entzündung im Achsenskelett bedingt, wobei die Sakroiliakalgelenke (SIG) initial besonders häufig betroffen sind. Meist in späteren Stadien kommt die Wirbelsäule hinzu, was strukturell dann zunehmend durch Knochenneubildung gekennzeichnet ist. Zum Gesamktonzept der Spondyloarthritiden gehören weitere Krankheitsmanifestationen wie Uveitis, Psoriasis und Colitis und Komorbiditäten wie kardiovaskuläre Erkrankungen und Osteoporose.
Für die axSpA gibt es seit 2009 die ASAS-Klassifikationskriterien, die die 1984 modifizierten New York-Kriterien abgelöst haben. Bei ersteren spielen über das konventionelle Röntgen hinaus erstmals mit Magnetresonanztomographie (MRT) festgestellte Veränderungen in der Bildgebung der SIG und auch der Nachweis von HLA B27 eine Rolle. Wichtig ist, dass es sich nicht um diagnostische Kriterien handelt, denn die gibt es nicht. In dieser Arbeit werden 10 Punkte aufgezeigt, die bei der Diagnosestellung berücksichtigt werden sollten.
The association of the human lymphocyte antigen B27 (HLA-B27) with ankylosing spondylitis (AS), also now called axial spondylarthritis (axSpA), was first described 50 years ago.
This article gives an overview of the available knowledge on the topic.
This is a narrative review based on the experience of the authors.
The HLA-B27 is a member of the HLA class I family of genes of the major histocompatibility complex (MHC). The prevalence of HLA-B27 in the central European population is approximately 8 %, i.e., the vast majority of carriers of HLA-B27+ remain healthy. The frequency of HLA-B27 shows a decline from north to south. The HLA-B27 explains only 30 % of the genetic burden of axSpA. The prevalence of the disease correlates with the frequency of HLA-B27 in the population, i.e., there are geographic differences. Approximately 60–90 % of patients with axSpA worldwide are HLA-B27+. Some 200 subtypes of HLA-B27 can be differentiated using the polymerase chain reaction (PCR). In Thailand and Sardinia two subtypes were found that are not associated with axSpA. The physiological function of HLA class I molecules is the defence of the organism against microbes. Microbial peptides are presented to the immune system, which can be specifically attacked by CD8+ T‑cells. Genetic polymorphisms of the enzyme endoplasmic reticulum aminopeptidase 1 (ERAP1), which breaks down peptides in the endoplasmic reticulum, are associated only with HLA-B27+ diseases.
The pathogenesis of axSpA is unclear but a major hypothesis is that of the arthritogenic peptides. In this it is assumed that potentially pathogenic foreign or autologous peptides can be presented by HLA-B27. If nothing else, HLA-B27 plays an important role in the diagnosis, classification and determination of the severity of axSpA.
Associations of HLA antigens with many of the rheumatic diseases have been established over the last two decades. Although these discoveries provide potential new insights into disease pathogenesis, the clinical utility of HLA typing has been limited. The major exception is that of HLA-B27 in the spondyloarthropathies, where clinical uses of HLA-B27 testing has permitted identification of a large spectrum of disease that was previously misdiagnosed and misclassified. HLA-B27 remains potentially useful in the diagnosis of atypical spondyloarthropathies because of its high frequency in patients with these diseases (yielding good sensitivity) and its relatively low frequencies in most normal populations (yielding good specificity). Its predictive value in individual cases, however, depends on the quality of the physician's assessment of the likelihood of a spondyloarthropathy. In patients with juvenile-onset arthritis, typing for HLA-B27, as well as several HLA-class II alleles (DR5, DR8, DP2, and DP3), may prove to be useful in diagnosis and classification; however, additional studies are necessary. HLA oligotyping of DNA in patients with early rheumatoid arthritis to determine homozygosity versus heterozygosity for the DRB1 susceptibility sequence promises a potential new parameter for predicting clinical disease severity, and thus the possible early initiation of more aggressive therapies. Additional studies are necessary, however, to determine the validity of this approach.
Finally, the future diagnosis, prevention, and treatments of these diseases may depend on the identification and manipulation of specific immune responses mediated by HLA molecules, thus making HLA typing for clinical purposes routine.
Despite impressive advances in our understanding of the natural history of the rheumatic diseases and their treatments, there remains much to be learned. The management of most of these diseases is far from satisfactory for either the clinician or patient. There is little distinction between clinical practice and clinical research. How much and what type of data one should collect clearly depends on the setting and on the clinical/research questions being asked. One must ensure that the literature is relevant to his or her practice. The corollary is that research must be derived from a variety of settings, including both the traditional researcher and the traditional clinician.
Family studies and investigation of the HLA associations have in recent years added to our understanding of the spondyloarthropathies. In regard to ankylosing spondylitis it is likely that B27 itself is the major susceptibility gene but that additional genes may play a secondary role. Heterogeneity of the B27 antigen has been demonstrated but has not yet been shown to be relevant to disease susceptibility. Haplotypes including Cw6 are related to susceptibility to psoriasis and psoriatic arthritis and although the risk for the arthropathy is increased in B27-positive individuals, there is some uncertainty regarding the association with other B locus antigens and further work is needed.
There is also uncertainty as to whether B27-associated disorders occur randomly within families, or whether particular disorders cluster in certain families and further evidence in this field would be of considerable interest.
Genetic studies, as here outlined, have not as yet had a major impact in clinical medicine but it is anticipated that a deeper understanding of the mechanisms of HLA-linked susceptibility genes and in particular of how they interact with environmental agents, will improve our ability to treat and possibly prevent the relevant diseases.
Der Leser wird nach der Lektüre dieses Beitrags Kenntnisse über die Infektätiologie der reaktiven Arthritis sowie die gegenwärtig bekannten Erreger ebenso besitzen wie über die heute gängigen pathogenetischen Hypothesen, die klinische Präsentation, den klinischen Verlauf und die gegenwärtig empfohlenen therapeutischen Maßnah-men. Besonderes Augenmerk wird dabei auf die möglichst frühe Diagnose und kom-plette diagnostische Abklärung zur Optimierung therapeutischer Maßnahmen und damit Verbesserung der Prognose gelegt.
Die entzündlich-rheumatischen Erkrankungen manifestieren sich als „Rheuma“ am Stütz- und Bewegungssystem und knüpfen insoweit an das vorige Kapitel an. Gemeinsam ist ihnen ein immunologischer Prozess, der zahlreiche weitere Organe mit einbeziehen kann, was das Spektrum möglicher Krankheitserscheinungen und folgen beträchtlich erweitert.
Saint-Hillier et al.1 typed 7 French patients for A and B loci antigens. When compared with a control population of unknown size, they found no significant difference between the 2 groups.
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.
Ankylosing spondylitis (AS), a prototype of spondyloarthritis (SpA), is a chronic inflammatory disease involving spine, peripheral joints and peri-articular soft tissues. The spectrum of SpA can be classified to 5 diseases categories: ankylosing spondylitis, psoriatic arthritis (PsA), reactive arthritis (ReA), inflammatory bowel diseases-associated arthritis, and undifferentiated spondyloarthritis (USpA). Common clinical features of SpA are chronic inflammatory arthritis over spine, sacroiliac joints, peripheral joints and enthesitis. Up to 45% of AS patients may have extra-articular manifestations, such as uveitis, psoriasis, bowel inflammation and nephropathy. The etiology is unknown, but probably related to genetics and immune dysregulation that was triggered by environmental factors, mainly infection and trauma. Management of AS are focused on control of chronic inflammation by non-steroidal anti-inflammatory drugs (NSAID), disease-modifying anti-rheumatic drugs (DMARD) and anti-tumor necrosis factor biological agents.
This new companion to Office Orthopedics for Primary Care, 3rd Edition, provides straightforward, in-depth, full-color guidance on the diagnosis of 52 of the most common musculoskeletal problems seen in todays clinical settings. It spells out exactly what to look for during the physical examination and in what sequence, providing readers with the knowledge they need to effectively diagnose these problems. Lavish, full-color photographs and line drawings enhance the text and make concepts easier to understand. Features the expertise of Dr. Bruce Carl Anderson, a world authority on orthopedic practice in primary care. Presents proven how-tos of diagnosis for the 52 most common orthopedic problems. Features detailed descriptions and lavish illustrationswith hundreds of color photographsto show every aspect of proper diagnosis. Provides comprehensive treatment reference tables that list best-practice treatments, procedures, and equipment, such as supports, braces, and casts. Gives cross-references to the companion volume, Office Orthopedics for Primary Care, 3rd Edition. Includes many at-a-glance tables showing diagnostic tips and features, clinical pearls, and differential diagnoses.
Objectif
– Explorer les zones d’incertitude des recommandations HAS, concernant la place du groupage HLAB27, dans le diagnostic de Spondylarthrite axiale.
Méthodes
– La procédure était la suivante : choix de la question, par un comité scientifique, selon la méthode Delphi ; revue systématique de la littérature, à partir de la base de données PubMed, jusqu’en avril 2011 ; présentation des résultats à un panel d’experts en Rhumatologie et discussion des résultats.
Résultats
– La recherche bibliographique a permis d’identifier 489 références dont 19 ont servi de base de travail. L’analyse a montré : une discordance entre les spécificités et valeurs prédictives issues des 9 cohortes transversales et celles issues des 4 études prospectives ; une bonne valeur prédictive négative dans les formes axiales ; un apport moindre dans les formes indifférenciées ; un risque de récurrence de Spondylarthrite axiale, chez les apparentés au premier degré, d’environ 8%, majoré à 20% si le sujet est porteur de l’antigène HLAB27 et à 60% s’il s’agit d’un co-jumeau monozygote HLAB27+.
Conclusion
– Utilisé seul, le groupage HLA est insuffisant pour établir quel patient répondra aux critères de classification d’une spondylarthrite. Son utilisation s’entend plutôt au sein d’un algorithme diagnostique (Berlin) ou de critères diagnostiques (ASAS). Toutefois il semblerait que les performances du groupage HLA utilisé dans ces outils, ont été établies sur des données ne permettant pas de répondre strictement à la question du diagnostic. La valeur diagnostique réelle du groupage HLAB27 doit être précisée dans des études dédiées aux critères ASAS ou à l’algorithme de Berlin.
A brief account of current knowledge of the major histocompatability complex (MHC) in man, named HLA, is followed by a review
of Class I antigen-associated rheumatic and other autoimmune diseases. Although of great theoretical interest, HLA B27 is
of relatively little value as a diagnostic test. It does appear, however, to be more frequently associated with severe disease,
and, in ankylosing spondylitis, with certain complications, such as iridocyclitis and cardiac involvement.
OBJECTIVE:Celiac sprue is associated with specific HLA-DQ genes (mainly DQ2). Because there are epidemiological and histopathological similarities between celiac sprue and microscopic colitis, we hypothesized that these syndrome may share an HLA genetic predisposition and pathogenesis.METHODS:The HLA-DQ genes of 25 patients with celiac sprue, 53 patients with the microscopic colitis syndrome, and 429 normal controls were typed and compared. Serum was analyzed for antigliadin and antiendomysial antibodies. Small intestinal biopsies were analyzed for signs of histopathology.RESULTS:HLA-DQ2 or DQ1,3 (the latter as DQ1,7,DQ1,8, or DQ1,9) were seen more frequently in both patient groups relative to controls. In patients with the microscopic colitis syndrome, serological tests for celiac sprue were weakly positive in 17%; mild inflammation of the small intestine without villous atrophy was present in 43%, and inflammation plus partial or subtotal villous atrophy was present in 27%.CONCLUSIONS:A shared set of predisposing HLA-DQ genes account for the epidemiological overlap of celiac sprue and microscopic colitis. Mild to moderate mononuclear cell inflammation of the small intestine, often accompanied by partial or subtotal villous atrophy, is frequent in patients with the microscopic colitis syndrome. Although further studies will be necessary to determine if this enteropathy is induced by dietary gluten, we speculate that the small intestinal but not colonic histopathology in patients with microscopic colitis is caused by immunological gluten sensitivity.
Objectives:
The pathogenesis of axial spondyloarthritis (axSpA) is still unclear. There is a strong association with HLA-B27 and other genes. Recently, anti-CD74 antibodies with specificity to a class II-associated invariant chain peptide (anti-CLIP-ABs) were found in axSpA patients. We examined the prevalence, sensitivity and specificity of anti-CLIP-ABs in axSpA in comparison with controls.
Methods:
Sera of axSpA and non-SpA patients were analysed for IgG-antibodies against CD74 by ELISA with specificity for CLIP developed in cooperation with AESKU Diagnostics (Germany). A cut-off of ≥4 SDs of arbitrary units (AU) from mean serum levels was used to differentiate the results. The laboratory workers were completely blinded for clinical data.
Results:
We analysed 145 sera from 94 axSpA and 51 non-SpA patients. AxSpA patients were more often male and younger. HLA-B27 status was available in 72 patients. Anti-CLIP-ABs were detected in 85.1% in axSpA but in only 7.8% in non-SpA patients (p≤0.0001). AxSpA patients showed higher levels of anti-CLIP-ABs versus non-SpA: mean 14.5 versus 0.8 AU (p≤0.0001). The sensitivity of anti-CLIP-ABs for diagnosing axSpA was 85.1%, specificity 92.2%, likelihood ratio (LR) LR+ was 10.8 and LR- was 0.08. Anti-CLIP-ABs and HLA-B27 were positive in 87.5% patients with axSpA, but only 14.9% were anti-CLIP-negative, while 23.6% were HLA-B27-negative.
Conclusions:
Anti-CLIP antibodies were strongly associated with axSpA. The LR for confirming axSpA by using anti-CLIP was even higher than by using HLA-B27. More studies using this promising new method in patients with non-radiographic axial SpA or peripheral SpA are needed to establish its usefulness in clinical practice.
Autoimmune chronic rheumatic inflammatory diseases are polygenic illnesses in which the inflammatory process mainly occurs in the synovial tissue, surrounding the joints. Dozens of inflammatory genes are upregulated or downregulated in each rheumatic disease. The genes of several of the molecules synthesized are often polymorphic and some of these polymorphisms have clearly been shown to be functionally relevant. In recent years monoclonal antibodies directed against some of the molecular targets have been developed, the first ones being the monoclonals against a key driver of synovial inflammation namely tumor necrosis factorα, followed by interleukin 1β, then interleukin 6 receptor and others. According to the background, the clinical benefits could be either partially driven by the pathobiological milieu, or by the polymorphisms of the genes encoding the target molecules. In this article the complex heterogeneity of the inflammatory genes regulating key molecules, which are targets of the therapeutic intervention with specific monoclonal antibodies is reviewed, along with the crucial data that could be obtained also on the inflammatory process by the ongoing clinical trials in which pharmacogenetics is mandatory.
Objective:
To compare the clinical, demographic, and serologic characteristics and the treatment of patients diagnosed with ankylosing spondylitis (AS) from Europe (EU) and Latin America (LA).
Methods:
We included 3439 patients from national registries: the Spanish Registry of Spondyloarthritis (REGISPONSER), the Belgian registry (ASPECT), and the Latin American Registry of Spondyloarthropathies (RESPONDIA). We selected patients with diagnosis of AS who met the modified New York classification criteria. Demographic, clinical, disease activity, functional, and metrological measurement data were recorded. Current treatment was recorded. The population was classified into 2 groups: patients with disease duration < 10 years and those with disease duration ≥ 10 years. A descriptive and comparative analysis of variables of both groups was carried out.
Results:
There were 2356 patients in EU group and 1083 in LA group. Prevalence of HLA-B27 was 71% in LA group and 83% in EU group (p < 0.001). We found a greater frequency of peripheral arthritis and enthesitis (p < 0.001) in the LA population; prevalence of arthritis was 57% in LA and 42% in EU, and for enthesitis, 54% and 38%. Except for treatment with anti-tumor necrosis factor (anti-TNF), the use of nonsteroidal antiinflammatory drugs (NSAID), corticosteroids, and disease-modifying antirheumatic drugs (DMARD), and the association of anti-TNF and methotrexate use showed a significant difference (p < 0.001) in the 2 populations.
Conclusion:
The principal differences in the clinical manifestations of patients with AS from EU and LA were the greater frequency of peripheral arthritis and enthesitis in LA group, the higher percentage of HLA-B27 in EU group, and the form of treatment, with a greater use of NSAID, steroids, and DMARD in the LA group.
The end of this century and the dawn of the new millennium are near, and we still don't fully understand the mechanism behind the remarkable association of HLA-B27 with spondy-loarthropathies, although it has been known for more than a quarter of a century. However, there has been a slow but steady progress in the field of spondyloarthropathies. Not all alleles that encode for the HLA-B27 serologic specificity are associated with susceptibility to develop a spondyloarthropathy. The number of known subtypes of HLA-B27 continue to grow; the latest three additions are HLA-B*2713, HLA-B*2714, and HLA-B*2715. It is becoming increasingly clear that the observed synovial and cartilage changes in spondyloarthropathies are mainly the result of an entheseal- rather than a synovial-based pathology, because the initial or primary inflammatory response is located at the enthesis, whereas synovitis is most likely triggered secondarily by locally released cytokines at the adjacent sites in the joint cavity. But we still don't know how ankylosis relates to HLA-B27. The conditions favoring the development of HIV-associated spondyloarthropathy are becoming less of a problem in North America, but this is not the case in some of the other regions of the world, such as Sub-Saharan Africa.
Objective
To determine the overall prevalence of spondylarthropathy (SpA) among whites.Methods
To screen for SpA symptoms, such as inflammatory back pain (IBP), joint swelling, psoriasis, and uveitis, or a specific family history, questionnaires were mailed to 348 blood donors (174 HLA-B27 positive and 174 HLA-B27 negative). From the responding 273 persons (78%; 140 B27 positive, 133 B27 negative), 126 were selected for further evaluation based on the symptoms reported. Of this group, 90 persons agreed to undergo physical examination (71.4%; 46 B27 positive, 44 B27 negative). There was no difference between the B27-positive and -negative groups in terms of age (mean ± SD 38.4 ± 10 versus 39.5 ± 11 years) and sex ratio (67% versus 68% were men). In addition, 58 donors (32 B27 positive, 26 B27 negative) agreed to undergo magnetic resonance imaging (MRI) of the sacroiliac joints. A diagnosis of SpA and ankylosing spondylitis (AS) was made according to the European Spondylarthropathy Study Group criteria and the New York criteria.ResultsSpA was diagnosed in 20 persons: 19 of 140 B27-positive (13.6%) and 1 of 133 B27-negative (0.7%) subjects (15 male and 5 female). AS was diagnosed in 9 persons (7 male and 2 female; 45%), undifferentiated SpA (USpA) in 7 (5 male and 2 female; 35%), psoriatic arthritis (PsA) in 3 (2 male and 1 female; 15%), and chronic reactive arthritis (ReA; Reiter's syndrome) in 1 (male; 5%). On the basis of a B27 frequency of 9.3% among the population of Berlin (3.47 million persons), the estimated prevalence of SpA was 1.9%, AS was 0.86%, USpA was 0.67%, and PsA was 0.29%. The relative risk of developing SpA in B27-positive subjects was calculated as 20.7 (95% confidence interval 4.6-94.2; P = 0.001). Of 58 persons with IBP, sacroiliitis was detected by MRI in 15 of 32 B27-positive (46.9%) and 1 of 26 B27-negative (3.9%) subjects (P = 0.002). Four of these 16 donors did not fulfill diagnostic criteria for SpA.Conclusion
With a calculated prevalence of 1.9%, spondylarthropathies are among the most frequent rheumatic diseases in the white population. HLA-B27 positive persons carry a 20-fold increased risk of developing SpA. AS and USpA are the most frequent SpA subtypes. Persons with IBP who are B27 positive have a 50% likelihood of having sacroiliitis.
OBJETIVO: Determinar la asociación causal entre parasitosis intestinal y artritis reactiva (ARe). MATERIAL Y MÉTODOS: Estudio de casos y controles. El grupo de casos comprendió 31 pacientes con diagnóstico de ARe internados en el Hospital Militar Central de Lima durante los años 1994-1995. El grupo control abarcó a 31 pacientes sin ARe. La información se recogió de las historias clínicas que correspondían tanto a personal civil como militar. RESULTADOS: En el grupo de casos, 11 pacientes (35,48%) tuvieron parasitosis intestinal; 12 pacientes (38,71%) presentaron eosinofilia que remitió con albendazol y/o metronidazol, con mejoría evidente del cuadro clínico; y 8 pacientes (25,81%) no tuvieron parasitosis ni eosinofilia. En el grupo control la proporción fue 7 (22,58%), 5 (16,13%) y 19 pacientes (61,29%), respectivamente. CONCLUSIÓN: Existe una fuerte asociación entre la exposición a parásitos intestinales y ARe (OR = 4,5; p <0,05), pudiendo existir un sinergismo en el efecto artritogénico debido a poliparasitismo. Los parásitos más frecuentemente hallados fueron Ascaris lumbricoides (7/11) y Ancylostoma duodenale (5/11).
Objective. To determine trends in the incidence and clinical presentation of ankylosing spondylitis first diagnosed between 1935 and 1989 among residents of Rochester, Minnesota, and in the survival of the patients.
Methods. Population-based descriptive study.
Results. The overall age- and sex-adjusted incidence rate was 7.3 per 100,000 person-years (95% confidence interval 6.1–8.4). The rate tended to decline between 1935 and 1989, but there was little change in the age at symptom onset or diagnosis over the 55-year study period. Overall survival was not decreased up to 28 years following diagnosis.
Conclusion. These data indicate that there is a constancy in the epidemiologic characteristics of ankylosing spondylitis and suggest that previously study results indicating changes may have been due to biases in patient selection and study design.
Objective. To evaluate the new magnetic resonance imaging (MRI) method of dynamic MRI with fast imaging in the diagnosis of sacroiliitis among patients with spondylarthropathy.
Methods. Fifteen patients with a history of inflammatory back pain without radiographic evidence of grade II or greater sacroiliitis (group 1), 25 patients with definite ankylosing spondylitis (group 2), and 12 patients with noninflammatory spinal pain (controls) (group 3) were examined. Dynamic MRI with fast imaging was performed after intravenous bolus injection of the contrast agent gadolinium—diethylenetriamine pentaacetic acid. The degree of enhancement was graded as representing acute sacroiliitis, latent sacroiliitis, or no sacroiliitis.
Results. Acute sacroiliitis was detected in 22 of 30 sacroiliac (SI) joints in group 1 patients and in 27 of 50 SI joints in group 2 patients; latent sacroiliitis was seen in 25 of 80 SI joints in patients from groups 1 and 2. No group 3 patient was found to have sacroiliitis.
Conclusion. Early sacroiliitis can be demonstrated by dynamic MRI in spondylarthropathy patients in whom abnormalities are not revealed by conventional radiography.
The microdroplet lymphocyte cytotoxicity test was examined thoroughly in an effort to increase the reproducibility of the test. The discrepancy rate in a large series of tests was reduced from 5.16% at the start of this study to the present 0.95% by introducing certain modifications in the technique. Variables connected with the isolation of lymphocytes, handling of antisera, quality of antisera, amount of complement, incubation temperature, duration of incubation, fixing of reactions, and reading of reactions were studied. The method which has resulted appears to be reproducible, simple, and readily usable on a large scale.
Ankylosing spondylitis is diagnosed once or twice in each 1000 males and one tenth as frequently in females, but the true prevalence is unknown. Indentification of genetic marker, HL-A W27, for susceptible persons has provided a tool facilitating epidemiologic studies and allowing identification of "control" populations without the marker. Evaluation by postal questionnaires, and pelvic radiography of 78 HL-A 27W-positive blood donors selected from a group of apparently healthy subjects revealed 14 who satisfied the criteria for definite ankylosing spondylitis. The prevalence was similar in both sexes. One hundred and twenty-six W27-negative controls matched for race, sex, and age failed to yield a single case. For a person of either sex with HL-A W27, there appears to be about a 20 per cent chance that ankylosing spondylitis will develop, suggesting a prevalence of 10 to 15 per thousand. Hitherto accepted figures may underestimate the frequency by a factor of 10 to 20.
SUMMARY Too much of the information required for rigorous assessment of the diagnostic value of a positive HL-A 27 test is not available.
Certainly there would seem to be no case for population screening, not least because effective prophylaxis is not possible.
At present sacroiliac radio-graphs have greater value in the clinical situation, and it seems unlikely that the contribution
they make to diagnosis will be challenged. The absence of the HL-A 27 antigen may have some value as an exclusion test, but
careful prospective studies are required, as well as a more detailed cost-benefit appraisal of this test.
The analysis and precise definition of HLA antigens is still problematical. Adequate characterised monovalent antibodies for the detection of individual HLA antigens are not available in the desired range. It would be desirable if all laboratories involved with HLA typing could use antibodies of identical specificity. It has been possible recently, with the mouse and rat, to produce monoclonal antibodies against MHS antigens, with the help of cell hybridisation.
The association between ankylosing spondylitis and HLA-B27 has been noted in all races that have thus far been studied; it tends to be strongest in whites and relatively weaker in blacks. Reiter's syndrome is also strongly associated with HLA-B27 in whites, but has not been well studied in blacks. Morris and associates have suggested the use of B27 typing in the clinical evaluation of white male patients with suspected Reiter's syndrome and have predicted that the test would be even more helpful in blacks. The results of a study of the diagnostic usefulness of B27 typing in white and black patients with Reiter's syndrome is reported.
The clinical features of ankylosing spondylitis (AS) were compared in 63 HLA-B 27 positive (+) and 15 B27 negative (-) individuals with this disease. There were no differences in age at onset, functional class, degree of deformity, pain, severity of X-ray changes, or frequency of peripheral joint involvement or of reconstructive orthopedic surgery. These data demonstrated that skeletal manifestations of AS were essentially the same in B27(+) and (-) patients, and provide no evidence for the speculation that AS in B27(-) patients is milder or is a different disease from that occurring in B27(+) patients. On the other hand, acute anterior uveitis was found to be significantly more common in B27(+) patients, a fact suggesting that the "uveitis of AS" may in fact be an independent condition occurring in B27(+) individuals, rather than a manifestation of AS per se.
This article has no abstract; the first 100 words appear below.
AS both the number and cost of clinical laboratory tests continue to increase at an accelerating rate,¹ physicians are faced with the task of comprehending and acting on a rising flood tide of information. We conducted a small survey to obtain some idea of how physicians do, in fact, interpret a laboratory result. Methods We asked 20 house officers, 20 fourth-year medical students and 20 attending physicians, selected in 67 consecutive hallway encounters at four Harvard Medical School teaching hospitals, the following question: "If a test to detect a disease whose prevalence is 1/1000 has a false positive rate of . . .
*Adapted from Schwartz2 and originally posed to one of the authors (W.C.) by N. K. Hollenberg.
† where PV is the predictive value of the positive result (i.e., the likelihood of disease), p denotes disease prevalence, Se the sensitivity (proportion of diseased persons who give positive results), and Sp the specificity (proportion of healthy persons who give negative results).
We are indebted to Drs. S. J. Adelstein, M. D. Altschule, S. W. Casscells, R. Fox, A. H. Goroll, N. K. Hollenberg, G. A. Lamb, B. Lown, S. J. Reiser, G. A. Silver and D. Z. Young for advice and criticism of the manuscript.
Source Information
From the Cardiovascular Laboratory, Harvard School of Public Health, and the Department of Medicine, Peter Bent Brigham Hospital (address reprint requests to Mr. Casscells at the Cardiovascular Laboratory, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115).
Reactive arthritis, defined as an acute arthritis associated with an infection elsewhere in the body and without the infecting microorganism being present in the joints, may follow infections of the intestinal and urinary tract. The intestinal pathogens Shigella, Salmonella, and Yersinia enterocolitica have been associated with reactive arthritis. In arthritis after enteritis caused by Campylobacter jejuni, a bacterium which has not been described as an aetiological agent in reactive arthritis, is described in a 20-yr-old male. The arthritis started two weeks after the onset of the enteritis, and the antibody titre against the isolated campylobacter significantly increased. Other known causes for acute arthritis could be excluded. Moreover, reactive arthritis after certain infections occurs especially in HLA-B 27 positive patients. This antigen was present in our patient.
Thirty-nine Caucasian women with definite or probable ankylosing spondylitis were tissue typed and the radiographic and clinical features were correlated with the presence of B27 (formerly W27). This investigation showed that the same strong positive correlation observed in men obtains in women between B27 and unequivocal radiographic changes. As such changes develop slowly in women, clinical and laboratory features were identified which were sufficiently characteristic to enable the diagnosis to be reached in advance of decreased spinal mobility. Immobility pain and stiffness and bilateral sacroiliac pain are the most characteristic features, but additional support is provided by the presence of any of the following: onset by age 30, a raised sedimentation rate, peripheral joint involvement, circumthoracic pain, family history, and iritis.
Three cases of Reiter's disease occurring in boys under the age of 16 are reported. One of these presented with a Salmonella enteritidis diarrhoea. This conforms to the 'dysenteric' form of Reiter's disease usually seen in Europe and rarely reported in England. Another presented with a monarticular arthritis of the knee, and the third has developed a chronic relapsing erosive arthritis as a result of sexually acquired Reiter's disease--an occurrence not previously reported in this age group. We draw attention to the frequency of diarrhoea in these children and the sex incidence of 1 female to 4--5 males, which agrees more with Reiter's disease of dysenteric origin than that acquired venereally.
Evidence for ankylosing spondylitis was sought by clinical, radiologic, and ophthalmologic examination in HL-A W27-positive men, aged 18 or older, selected from a tissue-donor population. Back pain of 3 months' duration or longer (P less than 0.05), back stiffness, restricted lumbar flexion and chest expansion, sacroiliac erosions (P less than 0.05) and sclerosis, and ophthalmologic sequels of anterior uveitis were found more often in the 24 men of the W27 group than in a control group of 31 men lacking this antigen. Based upon accepted criteria, 3 W27 persons had definite spondylitis and an additional 3 W27 persons and one control subject had findings strongly suggestive of spondylitis (P less than 0.05). This striking frequency, if extrapolated to the general population, would place approximately 1 of 4 W27-positive men at risk for this disease.
The recent extensive search for association between antigens of the major histocompatibility system, HL-A, and specific diseases was stimulated by the demonstration of genetic linkage between the murine major histocompatibility complex, H-2, and resistance to virus-induced leukæmogenesis, and specific immune responses. Though early data showed only weak associations with Hodgkin's and some other diseases, subsequent studies have shown very striking associations with a number of diseases having a presumptive or suspected autoimmune ætiology, including especially ankylosing spondylitis, psoriasis, coeliac disease, myasthenia gravis, and multiple sclerosis. These associations with the serologically detectable antigens of the HL-A system are identified by relative increases in the frequency of particular antigens in diseased individuals as compared with controls. The associations can be interpreted in terms of the effects of genes in the HL-A region which control immune responses that are critical for disease susceptibility. Direct methods for identifying these genes, which are now being developed, will greatly increase the facility with which such associations can be established. This will help clarify their nature and contribute to our understanding of the ætiology of the diseases concerned, as already demonstrated in the case of multiple sclerosis. HL-A linked specific immune-response genes are most probably important genetic factors predisposing to resistance or susceptibility to a variety of neoplastic, autoimmune, and infectious diseases in man.
Review of the literature and personal studies revealed clinical, familial and epidemiological evidence to support an hypothesis concerning the existence of a group of closely interrelated disorders which the authors termed the 'Seronegative Spondarthritides'. These disorders share a number of features including negative tests for rheumatoid factor; absence of subcutaneous (rheumatoid) nodules; peripheral inflammatory arthritis; radiological sacroiliitis with or without classical ankylosing spondylitis; a number of extra articular clinical characteristics such as psoriasiform lesions, ocular inflammation, genitourinary inflammation, buccal, intestinal and genital ulceration; a tendency to familial aggregation. Diseases fulfilling the criteria for the seronegative spondarthritis group include; psoriatic arthritis, Reiter's disease, ulcerative colitis, Crohn's disease, Whipple's disease, Behcet's syndrome and idiopathic ankylosing spondylitis. Although not included as seronegative spondarthritides, the relationship of the group to Still's disease, dysenteric arthritis and the Stevens Johnson syndrome is discussed. Particularly striking features within the seronegative spondarthritis network include: the central position of sacroiliitis as a common denominator to each member of the group; the close similarity between some cases of psoriatic arthritis and Reiter's disease; the close similarity between the intestinal arthropathies; the resemblance between intestinal arthritis, Reiter's disease and Behcet's syndrome; the clinical overlap between Reiter's disease and idiopathic ankylosing spondylitis. Finally, the practical importance of the seronegative spondarthritis concept was examined from the point of view of prognosis, diagnosis, treatment and aetiology.
The association between the histocompatibility antigen HLA-B27 and the seronegative spondylarthritides such as ankylosing spondylitis and Reiter's syndrome is dramatic. A question that arises in practice is, when should a clinician request HLA-B27 typing in the assessment of a patient with a rheumatologic complaint? Generally, diagnosis of these spondylarthropathies depends on history, clinical and radiologic examination, and, occasionally, confirmatory laboratory tests. This paper reviews the criteria for the diagnosis of the spondylarthritides, discusses the sensitivity and specificity of HLA-B27 typing in these conditions, analyzes the relation between HLA-B27 status and prognosis, and defines the role of genetic counseling. It is concluded th,t knowledge of the patient's HLA-B27 status provides only minimal help to the physician. Indiscriminate typing is to be deprecated.
Reiter's disease in its classic form is defined by the triad of arthritis, conjunctivitis, and urethritis and occurs predominantly in men. Recent descriptions have emphasized other ancillary findings: mucocutaneous lesions, plantar fasciitis, Achilles tendinitis, sausage digits, asymmetrical sacroiliitis, and an association with HLA-B27. This study describes 29 women followed over the past 4 years who have a rheumatic disorder most consistent with Reiter's disease. All 29 patients were seronegative, 72% presenting with an asymmetrical pauciarticular arthritis, and the majority evidenced lower extremity involvement. During the course of their illness, 52% of the patients developed either eye and/or urinary tract involvement. Additional features were mucocutaneous lesions in 8 patients, heel pain or Achilles tendinitis in 15 patients, sausage digits in 20 patients, and clinical sacroiliitis in 20 patients. HLA-B27 was positive in 59% of patients, and radiographic bone and joint abnormalities were present in 52% of the patients. The recognition of this group of patients has both therapeutic and prognostic implications, because they preferentially respond to indomethacin or phenylbutazone and often pursue a chronic course, albeit without widespread joint destruction.
HLA and Disease: A Comprehensive Review
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