Valor diagnóstico del HLA-B27 en las espondiloartropatías

Spondyloarthropathies are chronic inflammatory diseases that share a wide range of clinical features, including spondylitis, sacroiliitis, pauciarticular peripheral arthritis, and enthesopathy. The pathogenesis is not well known, although all these diseases (ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis in patients with inflammatory bowel disease, some forms of juvenile idiopathic arthritis, and undifferentiated spondyloarthropathies) seem to have common genetic bases. In the last few years, several theories on the pathogenesis of these diseases have been postulated. Many of these theories have implicated HLAB27, a molecule of the major histocompatibility complex, as a predisposing genetic factor. However, because some B27-positive individuals are disease-free while some B27 negative individuals develop one of these diseases, the pathogenic role of HLA-B27 remains unclear. To date, the diagnosis of spondyloarthropathies has mainly been based on clinical and radiographic criteria (New York modified criteria, European Study Group criteria, Bernard Amor criteria). The present review aims to describe current knowledge on the value of HLA-B27 in the diagnosis of spondyloarthropathies.     

Spondyloarthropathies in sub-Saharan Africa

HLA-B27 is virtually absent in most of the sub-Saharan Africa populations, and ankylosing spondylitis is rare; only a few patients have been reported from central and southern Africa. HLA-B27 was present in only one of 17 patients (6%). The disease shows clinical features that are similar to those observed in white HLA-B27-negative patients with ankylosing spondylitis; ie, the disease onset is later compared with HLAB27-positive patients, the patients rarely get acute anterior uveitis as one of the extra-articular manifestations, and familial occurrence of ankylosing spondylitis is rarely observed. There is a virtual absence of ankylosing spondylitis even in the west African countries of Gambia and Senegal, where 3% to 6% of the general population has HLA-B27. The epidemic of HIV infection in sub-Saharan Africa in recent years, however, has been associated with a dramatic upsurge in the prevalence of spondyloarthropathies other than ankylosing spondylitis, primarily reactive arthritis and undifferentiated forms of the disease, and less often psoriatic arthritis. HLA-B27, because of its rarity and virtual lack of association with the observed cases of spondyloarthropathy in this population, cannot be used as an aid to diagnosis of spondyloarthropathy in black Africans. Conversely, HIV infection is increasingly showing such a strong association with reactive arthritis, psoriatic arthritis, and undifferentiated spondyloarthropathies in sub-Saharan African populations that any patient with acute or chronic inflammatory arthritis may need to be tested for possible HIV infection. More research is needed on the evaluation of risk and protective factors in sub-Saharan African populations to better delineate the relative importance of genetic and environmental factors in the pathogenesis of spondyloarthropathies.     

Osteoporosis en las espondiloartropatías

Spondyloarthropathies are characterized by chronic inflammation of the axial skeleton and the entheses, sacroiliitis and peripheral arthritis predominantly in lower limbs. They are also associated with the human leucocyte antigen (HLA) B27.Osteoporosis is the most common metabolic bone disease. It is characterized by compromised bone strength, which predisposes an increased susceptibility to fractures, especially of the wrist, hip and spine. Patients with ankylosing spondylitis are at increased risk to develop vertebral fractures. The risk has been related with a low bone mineral density.We review this complication in the most representative entities of spondyloarthropathies: ankylosing spondylitis, psoriatic arthritis and arthopathy of inflammatory bowel disease.     

Clinical aspects, outcome assessment, and management of ankylosing spondylitis and postenteric reactive arthritis

The cause of ankylosing spondylitis remains unclear. Proof that this disorder is an autoimmune disease attributable to crossreactivity between bacteria and HLA-B27 is still lacking. Differences in endogenous peptide presentation by HLA-B27 subtypes might be relevant in the etiopathogenesis. Fractures of the osteoporotic spine contribute to morbidity. Spinal cord injury may occur. MR imaging enables identifying sacroiliitis earlier than plain radiography. Sweet syndrome has now been described in patients with ankylosing spondylitis and Crohn disease. Progress has been made in the assessment of ankylosing spondylitis. There are now core sets for different settings and validated instruments for functioning and disease activity that will enable demonstrating efficacy of new therapeutic interventions.The debate continues on classification of postinfectious and reactive arthritis. Bacterial antigens may be found in the inflamed joints; occasionally 16S ribosomal RNA is also demonstrated. Antibiotics seem not to be effective in postenteric reactive arthritis.More than 25 years have now elapsed since the association between ankylosing spondylitis and HLA-B27 was first described in 1973. The cause of this disease is still unknown, but a lot of progress has been made regarding the molecular structure of HLA-B27, the spectrum of disease, the clinical and radiographic assessment of ankylosing spondylitis, and its treatment. Recent advances in research on ankylosing spondylitis are reviewed here.     

Experimental spondyloarthropathies: Animal models of ankylosing spondylitis

Spondyloarthropathies (SpAs), including ankylosing spondylitis, are chronic inflammatory diseases of the axial skeleton. Genomic scans of SpA families revealed the overwhelming complexity of the disease, which appears to be under the control of over 20 chromosome loci, including the major SpA gene HLA-B27 within class I of the major histocompatibility complex (MHC). Animal models confirmed the primary role of MHC in SpA susceptibility and supported the hypothesis that certain enterobacterial infections can trigger SpA. Immunization of mice with proteoglycan aggrecan also can provoke SpA, thus providing the opportunity to study genetic and clinical details of the disease initiation.     

The HLA system and the arthropathies associated with psoriasis.

Histocompatibility typing was carried out in 74 patients with psoriasis and an inflammatory arthropathy. In 40 patients with peripheral arthropathy characterized by distal interphalangeal joint involvement, 13 (32-5%) were HLA-B27 positive, significantly higher than the control frequency (P = 5-8 X 10 (-6). 26 of the 40 patients did not have ankylosing spondylitis or radiological sacroiliitis and 7 were HLA-B27 positive, also significantly higher than in controls (P = 0-0049). All 7 patients with psoriasis and ankylosing spondylitis without peripheral arthropathy were HLA-B27 positive. The 10 patients with ankylosing spindylitis or radiological sacroliitis who were HLA-B27 negative all had peripheral arthropathy. It is suggested that being HLA-B27 positive increases the risk of a psoriatic patient developing both peripheral arthropathy and ankylosing spondylitis. In addition, some of the genes involved in susceptibility to psoriasis also have a role in the pathogenesis of both types of arthropathy. A hypothesis is put forward that some of the genes for psoriasis may be aetiologically important in some HLA-B27 negative patients with ankylosing spondylitis.     

The role of infection in the pathogenesis of spondyloarthropathies with special reference to human leukocyte antigen-B27

Spondyloarthropathies consist of many inflammatory diseases that are closely associated with human leukocyte antigen (HLA)-B27. One of these diseases is reactive arthritis (ReA), which is a joint inflammation that occurs after infections that are caused by certain gram-negative bacteria. The importance of these infections as causative agents of ReA has been clearly established. It is not clear, however, whether these infections contribute to the development of other forms of spondyloarthropathies. The exact mechanism by which HLA-B27 influences disease susceptibility in spondyloarthropathies remains to be determined. The role of HLA-B27 as an antigen-presenting molecule is certainly important in the pathogenesis of these diseases; however, recent data indicate that this molecule may exhibit other functions unrelated to antigen presentation, which may be important in the pathogenesis of ReA. In this paper, the authors summarize the current knowledge of the role of infection in the spondyloarthropathies.     

Sacroiliitis – it’s not all B 27

Summary We describe an HLA-B27 positive patient in whom posttraumatic pyogenic sacroilitis led to complete unilateral sacroiliac joint ankylosis in the absence of any signs indicative of HLA-B27 associated spondyloarthropathy. Sacroiliitis is the pathologic hallmark – and usually one of the earliest pathologic manifestations – of ankylosing spondylitis (AS). Bilateral sacroiliitis is typical for ankylosing spondylitis. The frequency of asymmetric sacroiliitis may be higher in other inflammatory disorders, e.g., reactive arthritis, Reiters syndrome, spondylitis associated with psoriasis, or infammatory bowel disease. Most but not all of these disorders show an increased prevalence among individuals who have inherited the HLA-B27 gene. In the context of this case, we discuss the differential diagnosis of unilateral sacroiliitis. Received: 25 August 1998 Accepted: 11 May 1999     

Animal models of spondyloarthritis

PURPOSE OF REVIEW: The aim of this article is to review new insights into spondyloarthritis obtained in animal models during the last year. RECENT FINDINGS: HLA-B27 misfolding has been demonstrated in HLA-B27/human beta2-microglobulin transgenic rats. HLA-B27 misfolding is associated with a typical unfolded protein stress response and with an interferon-response signature. Prebiotic treatment of these rats reduced colitis and arthritis. Proteoglycan-induced spondylitis is distinct from proteoglycan-induced arthritis. Specific susceptibility loci for proteoglycan-induced spondylitis have been demonstrated. Bone morphogenetic proteins are important in new cartilage and bone formation in ankylosing enthesitis. Psoriasis and psoriatic arthritis-like disease develops in conditional double JunB/c-Jun knockout mice. SUMMARY: Insights into the molecular signaling pathways driving HLA-B27 associated spondylitis, autoimmune spondylitis, ankylosing enthesitis and psoriasis, resulting from animal models, identify new and specific therapeutic targets in spondyloarthritis.     

HLA-B27 and genetic predisposing factors in spondyloarthropathies

With the mapping of the human genome having been completed, our ability to investigate and ideally better understand the genetic basis of rheumatic diseases is advancing at a rapid pace. Substantial evidence strongly favors a direct role for HLA-B27 in genetic susceptibility to ankylosing spondylitis and related spondyloarthropathies, although the underlying molecular basis has yet to be identified. HLA-B27 contributes only 16 to 50% of the total genetic risk for the disease, clearly indicating that other genes must be involved. However, no other putative disease genes have yet been absolutely proven. Potential genes include MHC (HLA class II, low molecular weight proteasome [LMP], transporter associated with antigen processing (TAP), tumor necrosis factor [TNF]-alpha, and major histocompatibility complex class I chain-related gene A (MICA), as well as non-MHC genes (IL-1RA, IL-6, IL-10, and CYP2D6). Genome-wide screens have identified other chromosomal areas of interest: 1p, 2q, 6p, 9q, 10q, 16q, and 19q. However, different studies have given conflicting results. HLA-B27 itself is a serologic specificity, which encompasses 25 different alleles that encode 23 different products (proteins): HLA-B*2701 to B*2723. These alleles may have evolved from the most widespread subtype, B*2705, and two of them, B*2706 in Southeast Asia and B*2709 in Sardinia, seem not to be associated with ankylosing spondylitis. The distinction between the disease associated and nonassociated subtypes may provide clues to the actual role of B27 in disease pathogenesis.     

Pathogenesis of ankylosing spondylitis and reactive arthritis

PURPOSE OF REVIEW: The hallmark of ankylosing spondylitis is acute and chronic spinal inflammation initiating in the sacroiliac joints, often coupled with enthesitis, presenting as chronic inflammation at the sites of ligamentous and tendinous insertions into bone. Peripheral joint synovitis can be a prominent feature as well. Reactive arthritis is a sterile synovitis arising after an extra-articular infection of enteric or urogenital tracts. HLA-B27 has been known for about the past 30 years to be associated with ankylosing spondylitis and reactive arthritis, but the pathogenesis of ankylosing spondylitis and reactive arthritis is still not well defined. Although the clinical manifestations of ankylosing spondylitis and reactive arthritis may differ, this update discusses the two diseases together and focuses on recent evidence in both. RECENT FINDINGS: With respect to HLA-B27 several recent studies address arthritogenic peptides, molecular mimicry, and aberrant forms of B27. Several candidate genes in addition to B27 have been implicated in recent genetic studies. With respect to bacterial infection, recent findings in bacterial antigenicity, host response through interactions of antigen-presenting cells, T cells, and cytokines are providing new understanding of host-pathogen interactions and the pathogenesis of arthritis. Endogenous host factors such as proteoglycans may play a role as autoantigens and contribute to chronic inflammation on that basis. SUMMARY: Recent advances provide additional new insights into distinct pathogenetic mechanisms in AS and ReA that arise from a complex interplay between genetic factors including HLA-B27 and environmental factors.     

Enthesitis in seronegative spondyloarthropathies with special attention to the knee joint by MRI: a step forward toward understanding disease pathogenesis

Seronegative spondyloarthropathies are a unique group of disorders sharing similar clinical characteristics (e.g., inflammatory back pain, spondylitis, sacroiliitis, uveitis, inflammatory bowel disease, skin rashes, and enthesitis). Clinical and genetic similarities suggest that they also share similar causes or pathophysiologies. Rheumatoid factor (RF) is characteristically negative in this group of disorders, hence collectively termed seronegative spondyloarthropathies (SpA). They include psoriatic arthritis, ankylosing spondylitis, reactive arthritis, ulcerative colitis, and Crohn’s disease. “Enthesitis”, the term used to describe inflammation at tendon, ligament, or joint capsule insertions, is considered a common feature in this domain and was included in the European Spondyloarthropathy Study Group criteria for the classification of SpA. Evaluation of entheseal-related changes at different joints by MRI became an important item on the research agenda in both differentiated and undifferentiated arthritis. Most of the research focused on MRI findings in the hand and wrist joints among patients with RA and SpA and support two patterns of inflammation “RA” phenotype where synovial involvement is the primary target of inflammation and “SpA” pattern where enthesitis comes first followed by synovitis. In this review, we summarize the literature on enthesitis in SpA and focus on MRI findings in the knee joint in the SpA group of disorders and subclinical synovitis among patients with skin psoriasis.     

Concepts and epidemiology of spondyloarthritis

The term 'spondyloarthritides' (SpA) comprises ankylosing spondylitis (AS), reactive arthritis, arthritis/spondylitis with inflammatory bowel disease, and arthritis/spondylitis with psoriasis. The main links between these diseases are an association with HLA-B27 and a similar clinical picture. Patients normally present with chronic low back pain or asymmetrical arthritis, predominantly of the lower limbs, and an overlap of these symptoms often occurs. AS is regarded as the most severe subtype. Recent attention has focused on earlier diagnosis of AS among patients with chronic low back, and this is becoming more important as effective therapies for early treatment have become available. AS is a disease of young people, normally starting in the third decade of life. The incidence and prevalence rates of AS, and of SpA as a whole, are strongly dependent and are directly correlated to the prevalence of HLA-B27 in a given population. Incidence rates of 0.5-8.2/100 000 population and prevalence rates of 0.2-1.2% have been described for AS, and about double these figures have been reported for SpA.     

Genetic epidemiology of psoriatic arthritis

Psoriatic arthritis (PsA) is defined as an inflammatory arthritis (IA) associated with psoriasis and is usually negative for rheumatoid factor. This ambiguous definition has impeded research into this subject, but as yet no agreed definition or classification criteria exist for PsA. Furthermore, there are those who question whether PsA exists as a distinct disease, or is a mere coincidence of inflammatory arthritides such as rheumatoid arthritis or ankylosing spondylitis with psoriasis. The pathogenesis of both IA and psoriasis is complex, involving interactions between many different genes and environmental etiological factors. It is likely that PsA is also a complex disease. The identification of genetic susceptibility factors unique to PsA over and above those that contribute to IA or psoriasis alone would put an end to speculation as to whether PsA exists as a distinct disease. In addition, it may aid in the development of novel therapies which target PsA specifically. This review summarizes the approaches taken to identify PsA susceptibility genes, and outlines some interesting regions which may harbor PsA susceptibility genes.     

Predisposing factors in the spondyloarthropathies: new insights into the role of HLA-B27

Spondyloarthropathies represent complex genetic diseases whose development is influenced by environmental factors. Estimates suggest that three to nine loci may be responsible for the majority of the genetic susceptibility to ankylosing spondylitis. The only susceptibility locus identified to date in multiple populations is HLA-B, where several HLA-B27 alleles (subtypes) are strongly associated with disease. Recent evidence implicates cytochrome P450 2D6 as a second locus, although its influence on overall risk appears small. Despite considerable efforts to define how HLA-B27 contributes to disease, its role remains enigmatic. Increasing evidence suggests it has effects that are unrelated to its physiologic function. The basis for this is unknown but may be a consequence of the unusual tendency of this allele to misfold.     

Arthritic Manifestations of Inflammatory Bowel Disease

Rheumatologic conditions associated with inflammatory bowel disease may be divided into four clinical categories. First, a unique form of peripheral arthritis occurs in 15-20% of patients with inflammatory bowel disease. The incidence is higher in Crohn's disease than in ulcerative colitis. This is a self-limited, nondeforming, seronegative arthritis that waxes and wanes with bowel flares. It characteristically involves knees and ankles. Persistent erosive monoarthritis is described. Second, spondylitis clinically and radiographically indistinguishable from idiopathic ankylosing spondylitis occurs in 3-6% of patients with inflammatory bowel disease. HLA-B27 positivity occurs in 53-75% of cases, fewer than in idiopathic spondylitis. Third, a bilateral, symmetrical sacroiliitis is seen in 4-18% of patients. This may not progress to clinical spondylitis. The fourth category encompasses rheumatologic complications of inflammatory bowel disease. These include granulomas of bones and joints, granulomatous vasculitis, clubbing, periostitis, amyloidosis, osteoporosis, osteomalacia, septic arthritis, and complications of corticosteroid therapy.     

Spondyloarthritis: update on pathogenesis and management

A great deal of progress has occurred in the past few years in elucidating the causes and designing new treatments for ankylosing spondylitis and other types of spondyloarthritis. In addition to the human leukocyte antigen (HLA)-B27 and other major histocompatibility complex (MHC) genes, chromosomal regions and genes elsewhere in the genome are being implicated both in disease susceptibility and severity. The various ways HLA-B27 may function in causing spondyloarthritis now are better understood to encompass not only antigen presentation but also other mechanisms, possibly all being operative in pathogenesis (misfolding of the HLA-B27 molecule, impaired intracellular killing of bacteria, and HLA-B27 itself serving as an autoantigen). Specific enteric and sexually acquired infections can trigger reactive arthritis, though no specific microbe has been identified in other forms of spondyloarthritis. Intestinal inflammation with impairment of the gut:blood barrier may be operative in driving ankylosing spondylitis and enteropathic arthritis. A number of treatments have been tried in spondyloarthritis, including older agents such as methotrexate and sulfasalazine but also newer drugs such as pamindronate. The recent introduction of tumor necrosis factor (TNF) blockers in the treatment of spondyloarthritis has offered the most hope in not only relieving symptoms and signs of both peripheral arthritis and enthesitis but also spinal disease, which often has been refractory to other agents. Their high cost and considerable side effect profile, however, have necessitated the establishment of guidelines for their use in these diseases in order to target the patient in whom they are likely to have the most benefit.     

Genetic aspects of ankylosing spondylitis

There is substantial evidence strongly favouring a direct role for HLA-B27 in genetic susceptibility to ankylosing spondylitis (AS) and related spondyloarthropathies (SpA), although the underlying molecular basis has yet to be identified. HLA-B27 itself is a serologic specificity that encompasses 26 different alleles that encode 24 different subtypes - HLA-B*2701 to B*2725, with the exclusion of B*2722. [The B*2722 allele was deleted as an official WHO allele in April 2002, with a note that the reference cell has been shown to have the same sequence as B*2706. Thus, from now on, with this deletion of B*2722, there will be a "hole" among the HLA-B*2701 to B*2725 group of alleles]. The 24 HLA-B27 alleles (subtypes) seem to have evolved from the most widespread subtype, B*2705. Two B27 alleles have been reported to lack association with AS: B*2706 among Southeast Asian populations, and B*2709 among Sardinians. The distinction between the disease-associated subtypes and those that are not disease-associated may provide some clues to the actual role of HLA-B27 in disease pathogenesis. Genetic family studies in populations of European descent indicate that HLA-B27 contributes only 16 % of the total genetic risk for the disease. The genes in the Major Histocompatibility Complex (MHC) as a whole, that includes HLA-B27, account for about half of the genetic susceptibility for AS. This clearly indicates the presence of additional disease predisposing genes in the MHC region on chromosome 6, and genome-wide studies have identified many areas of interest on other chromosomes that may contain additional disease predisposing genes. Additional studies emanating from the recent mapping of the human genome is expected to lead to better understanding of the genetic basis of these and other rheumatic diseases. Genetic counselling and the use of HLA-B27 typing as an aid to diagnosis are also reviewed.     

Predisposing factors in the Spondyloarthropathies: New insights into the role of HLA-B27

Spondyloarthropathies represent complex genetic diseases whose development is influenced by environmental factors. Estimates suggest that three to nine loci may be responsible for the majority of the genetic susceptibility to ankylosing spondylitis. The only susceptibility locus identified to date in multiple populations is HLA-B, where several HLA-B27 alleles (subtypes) are strongly associated with disease. Recent evidence implicates cytochrome P450 2D6 as a second locus, although its influence on overall risk appears small. Despite considerable efforts to define how HLA-B27 contributes to disease, its role remains enigmatic. Increasing evidence suggests it has effects that are unrelated to its physiologic function. The basis for this is unknown but may be a consequence of the unusual tendency of this allele to misfold.     

Multiple sclerosis during adalimumab treatment in a case with ankylosing spondylitis

Ankylosing spondylitis is a chronic and progressive inflammatory disease involving the sacroiliac joints with HLA-B27 positivity in 85 % of the patients and radiologically evidence of sacroiliitis. It is associated with several extraarticular manifestations, but neurological complications are rare. Occurrence of multiple sclerosis in patients with ankylosing spondylitis has been reported in limited cases. Adalimumab, a TNF-α antagonist, offers a significant improvement in ankylosing spondylitis and is considered to be less immunogenic and more tolerable than other TNF-α blockers. A case of multiple sclerosis coexisted with HLA-B27 positive ankylosing spondylitis after treated with adalimumab was reported.