Biomedical subjects
A Keat
Publications and source records attributed to A Keat.
Search for infective agents in undifferentiated oligoarthritis in Papua New Guinea.
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ABC of rheumatology. Spondyloarthropathies.
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HIV and overlap with Reiter's syndrome.
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Improving prescribing of non-steroidal anti-inflammatory drugs in hospital: an educational approach.
An assessment has been undertaken of the effect of an educationally-based voluntary prescribing policy on the overall prescribing of NSAIDs in two acute hospital units. The policy engendered a fall in district expenditure on these drugs of 12% over 1 year. The long term impact of the policy was studied after 3 years within one area of hospital prescribing, the Accident and Emergency (A & E) department. At the time of formal appraisal, a high degree of compliance with the agreed policy, of greater than 95%, was being maintained. The effect of regular audit sessions between prescribers, specialist clinicians and pharmacists was studied in detail over a period of 30 weeks. A reduction in total NSAID prescribing of 40% was achieved after a single session. A change in junior medical staff was associated with a fivefold increase in prescriptions for NSAIDs, which was not sustained. Total A & E prescribing remained static over the period of study. The audit process was also associated with a reduction in analgesic prescribing in general. The results of this study indicate that an educationally-based system for improving prescribing can change prescribing habits in the short term; these can be maintained in the longer term provided that the policy is continually monitored and reinforced by regular appraisal meetings with specialist clinicians and pharmacists. It is suggested that this educational approach can readily be adapted to the primary care setting, with general practitioners rather than specialists taking the leadership role. This would encourage the achievement of common prescribing strategies between hospitals and community that are not wholly financially led.
TB or not TB?: That is the question.
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Extra-genital Chlamydia trachomatis infection as sexually-acquired reactive arthritis.
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Reactive arthritis: the role of bacterial antigens in inflammatory arthritis.
For more than 100 years it has been suspected that bacteria or products derived from them are deposited in joints and cause arthritis without suppuration. Over this time a vast amount of evidence, much of which is still unchallenged, has accumulated to demonstrate that whole bacteria and subcellular bacterial elements do pass, under certain circumstances, from sites of mucosal colonization or infection into the circulation and thence into joints. Similarly, experimental studies have demonstrated that the deposition of both inert material and bacterial components within synovium is sometimes, but not always, associated with the development and persistence of synovitis. In human reactive arthritis aseptic synovitis follows localized bacterial infection in the gut or genitourinary tract. A genetic predisposition, associated with the HLA B27 antigen, is recognized, and interaction between class I HLA determinants and bacteria-derived antigens may underlie the development of arthritis. Although much remains to be learned about the dissemination of antigens from the primary site of infection in reactive arthritis, strong evidence implicates the deposition of antigenic elements of Chlamydia, Yersinia, Salmonella and perhaps other micro-organisms within the synovium. Immunological findings support the notion that such antigens are being presented within the joint and participating in the induction and/or maintenance of synovitis. It is not yet clear whether such bacteria are complete or viable or whether persistence at an extra-articular site is important to the persistence of arthritis. The possibility that reactive arthritis, and perhaps other forms of seronegative arthritis also, is caused and perpetuated by bacterial antigens within the joint poses new questions about the role of HLA B27 in pathogenesis. It also raises important and exciting issues regarding treatment. Already, studies of antimicrobial therapy have yielded encouraging initial findings, and it is now possible to design and evaluate therapies aimed at blocking specific antigen recognition within the joint.
Infections and the immunopathogenesis of seronegative spondyloarthropathies.
Evidence is accumulating for invasion of joints by bacterial antigens in the seronegative spondyloarthropathies. In spite of the inability to isolate bacteria directly from joint material, indirect evidence, provided by antibody and cellular immune studies, points to a local response to local antigen within the joint. Using monoclonal or polyclonal antibodies, several groups have reported detection of bacterial antigens in synovial fluid cells and synovium itself both in reactive arthritis and in undifferentiated forms of seronegative arthritis. There appear to be direct parallels with animal models insofar as bacterial persistence and arthritogenicity are concerned. To date, however, attempts to detect bacterial DNA in joint material, with the possibility of viability that such findings might imply, have been negative.
Synovial T lymphocyte-specific immune response to Chlamydia trachomatis in Reiter's disease.
We studied the lymphocyte proliferative response to Chlamydia trachomatis in Reiter's syndrome (RS) compared with that in other rheumatic diseases. RS patients showed significantly increased C trachomatis-specific synovial fluid (SF) T cell proliferation. Proliferating cells were found in both CD4+ and CD8+ T cell subsets. The SF lymphocyte proliferative response to C trachomatis in RS was inhibited by anti-class I and class II major histocompatibility complex monoclonal antibodies, while the response to tuberculin purified protein derivative was inhibited only by anti-class II monoclonal antibodies. T cell receptor gamma/delta-bearing T cells were not consistently increased in RS SF compared with peripheral blood, nor did such cells consistently expand upon in vitro culture with C trachomatis. Finally, there was no correlation between the cellular immune response and levels of antibody to C trachomatis antigens. Our results indicate that a specific T cell response to C trachomatis within the joint plays a role in the pathogenesis of RS.
The distribution and functional properties of dendritic cells in patients with seronegative arthritis.
Dendritic cells (DC), potent antigen-presenting cells, are known to be increased in numbers in inflammatory lesions in rheumatoid arthritis and juvenile chronic arthritis. In this study, patients with seronegative arthritis were studied; the distribution and functional properties of DC enriched low density cells (LDC) from peripheral blood (PB) and synovial fluid (SF) were compared. The composition of LDC from both sources was similar, comprising approximately 30% DC, 60% monocytes with few T lymphocytes. SF was significantly enriched for LDC compared with paired peripheral blood (P less than 0.0001) or peripheral blood from healthy controls (P less than 0.001). In contrast, patient PB contained fewer LDC (P less than 0.05) overall than healthy controls. LDC from both sources were potent simulators of allogeneic PB T cells in a mixed leucocyte reaction (MLR), but in four out of 10 patients SF LDC were significantly more stimulatory. In autologous MLRs (AMLRs) SF T cells were not stimulated by either LDC population. This anergy of T cells was confined to the joint as patient PB T cells showed an AMLR response to PB LDC which was similar to that seen in cells from healthy controls. PB T cells also responded to SF LDC; in a minority of patients SF LDC caused significantly greater stimulation in AMLR than PB LDC and the possibility is discussed that this may represent presentation of antigen acquired in vivo.
Peripheral blood and synovial fluid T cells differ in their response to alloantigens and recall antigens presented by dendritic cells.
Properties of T cells from inflammatory lesions were analysed by comparing the response of peripheral blood (PB) and synovial fluid (SF) T cells from 19 patients with a range of arthropathies to enriched allogeneic dendritic cells (DC) in a primary mixed leucocyte reaction (MLR). In 17 patients the proliferative response of SF T cells was significantly (P less than 0.05) less than that of PB lymphocytes. The reduced response of SF T cells was observed in all disease categories studied and could not be attributed to differences in cell number requirements or response kinetics. Addition of recombinant interleukin-2 enhanced the response of SF T cells in a dose-dependent manner. Cell mixing experiments suggested that active suppression was not the underlying mechanism of the poor MLR response of SF T cells. In contrast to the MLR response. SF T cells were able to mount vigorous proliferative responses to recall antigen presented by autologous antigen-presenting cells. The possibility is discussed that T cells compartmentalized at inflammatory lesions are a unique population with a diminished ability to interact with DC and respond to primary stimuli but an ability to respond to secondary antigenic challenge.
Reiter's syndrome and associated arthritides.
Several distinct arthritic syndromes now have been recognized in HIV-infected persons. These comprise seronegative spondarthritis, including classic Reiter's syndrome and psoriatic arthritis associated with HLA-B27, and undifferentiated arthritis usually confined to the lower limbs, unassociated with other lesions, and unrelated to any known genetic marker. In such cases great care should be taken to exclude infection. In addition, a syndrome of short-lived but sometimes severe arthralgias also occurs. Spinal pain is a major problem in some patients but ankylosing spondylitis appears to be rare among this group. Psoriasis probably occurs more often in the HIV-infected group than in the population in general and may be especially severe in those patients with arthritis. Arthritis has been reported in the United States, Europe, and Africa among persons considered to be at high and low risk for HIV infection. Arthritis can occur at any stage of HIV infection, but the true prevalence of arthritic syndromes and the nature of their association with HIV infection remains unclear. In view of the development of Reiter's syndrome in some patients, precipitating bacterial infections have been sought as the culprits. In a minority of cases, shigella, yersinia, and campylobacter infections have been implicated, but in the majority of cases, no specific infection has been identified. In most patients depletion of circulating CD4-positive lymphocytes is present by the time that arthritis is detected, but only limited data on synovial immunopathology are available. In some patients changes of nonspecific chronic synovial inflammation are present and synovial fluid cell counts are high. In other patients evidence of inflammatory changes is minimal. Human immunodeficiency virus has been isolated from joint fluid and identified in large mononuclear, probably dendritic, cells and lymphocytes. Synovium from patients dying with AIDS but with apparently normal joints also shows significant abnormalities that could lead to joint disease in long-term survivors. The possibility of a viral etiology of arthritis in some cases is suggested by the induction of arthritis in animals by lentivirus infection; it also is possible, however, that HIV enhances the effect of mechanisms that can operate in the absence of HIV infection. Conventional treatments of rheumatic lesions, including intraarticular steroids, appear to be safe and reasonably effective. Anecdotal evidence suggests that treatment with methotrexate and azathioprine leads to exacerbation of HIV disease and should be avoided.
Sexually transmitted arthritis syndromes.
Sexually transmitted infections may provoke a wide variety of rheumatic lesions. Disseminated N. gonorrhoeae infection leads to septic arthritis, which may be rapidly destructive but which responds promptly to appropriate antibiotic therapy. In contrast, both gonococcal and nongonococcal infections may lead to aseptic "reactive" arthritis or Reiter's syndrome. Inheritance of HLA B27 confers a relative risk of 30 to 50 times for the development of this condition. The demonstration of C. trachomatis antigen in joint material from a minority of patients suggests that direct interaction between microbial components and class I HLA antigens in the joint may be central to the pathogenesis of this disease. Arthralgia and arthritis occur in up to 50% of individuals in the prodrome of hepatitis B infection. Joint symptoms may be accompanied by urticarial or cutaneous vasculitic lesions, especially on the legs; both features resolve with the onset of jaundice. Hepatitis B infection is also a major cause of necrotizing vasculitis, which may or may not be associated with overt hepatitis. Seronegative arthritis, including Reiter's syndrome, psoriatic arthritis, and undifferentiated arthritis, a Sjögren's-like syndrome, vasculitis, and myopathies have been described in association with HIV infection. It is clear that synovitis occurs in those patients despite the fact that HIV is present in immune cells within the joint during inflammatory arthritis and that both antigen presentation and lymphocyte responsiveness within the joint are impaired. Nevertheless, synovitis may occur in the presence of marked CD4-positive lymphocyte depletion. Rheumatic syndromes, including arthralgia, inflammatory arthritis, and neuropathic arthritis, may occur during any stage of congenital or acquired syphilis. Syphilitic synovitis responds well to antibiotic therapy, but neuropathic lesions cannot be treated effectively. Septic arthritis has rarely been described as a complication of disseminated Mycoplasma or Urea-plasma infections, and joint lesions sometimes associated with erythema nodosum have also been reported in lymphogranuloma venereum and granuloma inguinale.
HLA-B27, arthritis and spondylitis in an isolated community in Papua New Guinea.
Rheumatic complaints in a sample of 109 individuals from an isolated community in Papua New Guinea were documented and 92/109 were tissue typed for HLA-B27. Eleven (10.1%) subjects had active peripheral arthritis, but 38 (34.9%) had previously suffered an episode of arthritis. In those with current peripheral arthritis, 6/10 (60%) were HLA-B27 positive compared to 15/58 (25.9%) with no history of arthritis (P less than 0.05). In total, 16/34 (47.1%) with either current or a previous history of peripheral arthritis were HLA-B27 positive compared to the 15/58 (25.9%) with no history of arthritis (P less than 0.05). Back pain was common. In 84/109 individuals the cause was mechanical injury; 24/72 (33.3%) of these were HLA-B27 positive. Ankylosing spondylitis was identified in one HLA-B27-negative woman.
Cross-reactive epitope with Klebsiella pneumoniae nitrogenase in articular tissue of HLA-B27+ patients with ankylosing spondylitis.
Synovial tissues from patients with ankylosing spondylitis or reactive arthritis were examined by an immunoperoxidase technique, using antisera to synthetic peptides representing antigens shared between HLA-B27.1 and Klebsiella pneumoniae nitrogenase. With either antiserum, all HLA-B27+ patients with synovial inflammation showed strong immunoperoxidase staining in synovial lining cells, vascular endothelium, and infiltrating inflammatory cells. These findings indicate that antigens showing cross-reactivity between HLA-B27.1 and Klebsiella nitrogenase epitopes are strongly expressed within inflamed synovial tissues of HLA-B27+ patients.
Chlamydia trachomatis in reactive arthritis.
Evidence of deposition of chlamydial antigen in the joint was sought in 10 patients (9 of them male) with classic sexually acquired reactive arthritis, 15 women with unclassified seronegative oligoarthritis involving the knee and 15 individuals with established rheumatic disorders not associated with genital-tract or other infections. Using a fluorosceinated monoclonal antibody to the major outer membrane protein of Chlamydia trachomatis (MicroTrak, Syva) in a direct immunofluorescence test, particulate antigen with physical characteristics of chlamydial elementary bodies was seen in synovial fluid cell smears or synovial biopsies, or both, from 6, 5, and 0 patients, respectively. No typical chlamydial intracellular inclusions were seen. Corroborative evidence of recent chlamydial infection was provided by the finding of high titres of serum chlamydial antibody in all antigen-positive patients with sexually acquired reactive arthritis, including 3 from whom a genital-tract isolate was obtained, and 3 of the 5 women with unclassified arthritis. It is postulated that Chlamydia trachomatis organisms reach the joint during acute genital-tract infection, and the processing and presentation by class I major histocompatibility determinants of chlamydial antigens is a critical step in the initiation of reactive arthritis in some patients.
Synovial expression of HLA-B27 related antigens in ankylosing spondylitis.
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