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J Highton

Publications and source records attributed to J Highton.

At least 19 recordsLinked to original sources
PubMed2007

Pulmonary rheumatoid nodules demonstrating features usually associated with rheumatoid synovial membrane.

OBJECTIVES: To describe the unusual immunohistological characteristics of two pulmonary rheumatoid nodules showing ectopic lymphoid follicles and the features normally associated with rheumatoid synovial membrane, and to discuss the implications of this novel observation. METHODS: Two formalin-fixed wax-embedded pulmonary rheumatoid nodules were processed for immunohistology. RESULTS: The central structure of the pulmonary nodules was typical of that uniformly expected in a rheumatoid nodule with central necrosis surrounded by a palisade of macrophages. However, a feature not previously observed in nodules was the presence of lymphoid aggregates containing B lymphocytes and, in some cases, showing characteristic features of lymphoid follicles. CONCLUSIONS: The presence of B lymphocytes and the development of ectopic lymphoid follicles in rheumatoid nodules have not been described previously. It is similar to synovial membrane, and contrasts with the expected structure of subcutaneous nodules where B cells and lymphoid follicles are normally absent. These observations establish that the morphology of rheumatoid nodules can vary in different tissues. They further suggest that the inflammatory process in the nodule and synovial membrane are likely to be similar, and that the characteristics of different tissues may be an important determinant of apparent differences between inflammatory lesions in synovial membrane and extra-articular nodules in rheumatoid arthritis.

B-Lymphocytes↗
PubMed2006

Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis.

A pragmatic approach that balances the benefit of a whole-genome association (WGA) experiment against the cost of individual genotyping is to use pooled genomic DNA samples. We aimed to determine the feasibility of this approach in a WGA scan in rheumatoid arthritis (RA) using the validated human leucocyte antigen (HLA) and PTPN22 associations as test loci. A total of 203 269 single-nucleotide polymorphisms (SNPs) on the Affymetrix 100K GeneChip and Illumina Infinium microarrays were examined. A new approach to the estimation of allele frequencies from Affymetrix hybridization intensities was developed involving weighting for quality signals from the probe quartets. SNPs were ranked by z-scores, combined from United Kingdom and New Zealand case-control cohorts. Within a 1.7 Mb HLA region, 33 of the 257 SNPs and at PTPN22, 21 of the 45 SNPs, were ranked within the top 100 associated SNPs genome wide. Within PTPN22, individual genotyping of SNP rs1343125 within MAGI3 confirmed association and provided some evidence for association independent of the PTPN22 620W variant (P=0.03). Our results emphasize the feasibility of using genomic DNA pooling for the detection of association with complex disease susceptibility alleles. The results also underscore the importance of the HLA and PTPN22 loci in RA aetiology.

Arthritis, Rheumatoid↗
PubMed2006

Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports.

BACKGROUND: Pneumonitis has very rarely been observed in patients taking leflunomide in clinical trials. Evidence is emerging that it is more frequent in clinical practice. AIM: The aim of this study was to investigate voluntary reports of suspected respiratory reactions to leflunomide held by the New Zealand Pharmacovigilance Centre (NZPhvC) and the Australian Adverse Drug Reactions Unit (ADRU) to ascertain if they fulfilled the criteria for pneumonitis and to define characteristics of this reaction. METHOD: Reports of respiratory adverse reactions attributed to leflunomide and received by the NZPhvC and the ADRU were analysed to identify those that were likely to be pneumonitis based on the criteria of Searles and McKendry. Features of these reports were examined to provide further information about this adverse reaction. RESULTS: The NZPhvC and the ADRU received 14 reports considered to be pneumonitis occurring in patients taking leflunomide. Two case reports fulfilled the Searles and McKendry criteria for definite or probable hypersensitivity pneumonitis. The patients in the remaining reports had radiological evidence of pulmonary infiltrates, an acute respiratory illness and no evidence of precipitating infection. In two cases the patients were taking leflunomide alone; one improved when it was withdrawn. In the other 12 cases, patients were taking leflunomide in combination with methotrexate. In nine of these 12 patients pneumonitis occurred after leflunomide was added to methotrexate, usually within 12-20 weeks. One of the two patients who died had possible previous methotrexate pneumonitis. Leflunomide washout with cholestyramine was used to treat three patients, one with life-threatening illness, with good results. CONCLUSION: This case series supports observations that leflunomide can cause pneumonitis either as monotherapy or in combination with methotrexate. The case histories indicate that prompt recognition is important to avoid life-threatening disease and support the use of cholestyramine to remove leflunomide.

Adult↗
PubMed2005

The use of the hand anatomic index to assess deformity and impaired function in systemic sclerosis.

To determine the "hand anatomic index" (HAI--a quantitative measure of hand deformity) in systemic sclerosis (scleroderma) and to compare it with the other measures of hand deformity and functional impairment. The HAI (measure of open hand span minus closed hand span/lateral height of hand) was determined in 30 patients with scleroderma and compared with hand deformity (as assessed by two independent rheumatologists) and with the Health Assessment Questionnaire (mHAQ), hand strength and prehensile gripability data. The HAI was confirmed as a reliable measure which clearly distinguished patients with increasing hand deformity and separated patients with diffuse scleroderma (n=12) from limited scleroderma (n=18), P=0.005. The HAI correlated significantly with measures of global functional impairment (as measured by the mHAQ) r=-0.46, P=0.01, hand strength r=0.51, P=0.0001 and prehensile gripability, r=-0.37, P=0.05 but neither with disease duration r=-0.16, P=NS nor age at disease onset r=0.20, P=NS. It was estimated that the HAI accounts for ~25% of the total global disability (as measured by HAQ). Measurement of the HAI in scleroderma provides a reliable and objective measure reflecting variable degrees of hand deformity and functional impairment and might provide a valid clinical outcome measure in patients with this disabling disorder.

Adult↗
PubMed2005

Clinical characteristics of an anatomical hand index measured in patients with rheumatoid arthritis as a potential outcome measure.

OBJECTIVES: To determine the clinical characteristics of an anatomical hand index previously reported as a potential measure of joint deformity and outcome in patients with rheumatoid arthritis. METHODS: The hand index (open hand span - closed hand span/lateral height of the hand) was measured in a cross-sectional study of 145 out-patients with rheumatoid arthritis with disease durations 0-55 yr. Subsets of patients were restudied at mean follow-ups of approximately 9 months and 4 yr. RESULTS: The hand index fell gradually with disease duration. Correlations were demonstrated with the Sharp index (r = - 0.39, P = 0.000) and to a lesser extent with disease activity score (r = - 0.28, P = 0.001). At 260 +/- 115 days the hand index worsened by 0.09 units (P = 0.09, NS). At 51.6 +/- 5.4 months the index showed a fall from 1.96 +/- 0.73 to 1.61 +/- 0.65 (P = 0.000). During the same interval the Sharp index increased from 60 +/- 68 to 80 +/- 71 (P = 0.000). CONCLUSIONS: Measurement of simple hand dimensions can demonstrate worsening of hand deformity with time in patients with rheumatoid arthritis. We suggest that more sophisticated analysis of digital hand images, as used in our original study, might yield additional information and increase the sensitivity of an anatomical hand index as an outcome measure in rheumatoid arthritis.

Anthropometry↗
PubMed2004

Evidence for negative association of the chemokine receptor CCR5 d32 polymorphism with rheumatoid arthritis.

BACKGROUND: Ligands of chemokine receptor CCR5, including MIP-1 alpha, MIP-1 beta, and RANTES, have been implicated in rheumatoid arthritis. OBJECTIVE: To test whether CCR5 d32 polymorphism has a negative association with rheumatoid arthritis in a New Zealand cohort. METHODS: 516 white patients with rheumatoid arthritis and 985 healthy controls were investigated by PCR amplification of the region flanking the known CCR5 d32 deletion, and the frequencies of CCR5 d32 compared. An early rheumatoid arthritis (ERA) cohort of 92 patients was followed prospectively for two years; disease severity and outcome were correlated with CCR5 d32 status. RESULTS: 12 control subjects (1.2%) were homozygous for d32; no d32 homozygous rheumatoid patients were detected (p = 0.012); 56 patients (10.9%) were heterozygous for the d32 polymorphism (d32/wt), compared with 169 controls (17.2%) (p = 0.0011). The CCR5 d32 allele frequency was lower in the rheumatoid patients than in the controls (frequencies of 0.054 and 0.098, respectively; p = 3.7 x 10(-5)). The frequency of CCR5 d32 did not differ significantly according to disease severity or outcome in the prospective ERA cohort, nor with HLA-DRB1 status. CONCLUSIONS: This study provides further evidence for a protective effect of the CCR5 d32 variant on rheumatoid arthritis, consistent with a role for CCR5 and its ligands in disease pathogenesis.

Arthritis, Rheumatoid↗
PubMed2004

A randomised placebo controlled trial of delipidated, deglycolipidated Mycobacterium vaccae as immunotherapy for psoriatic arthritis.

OBJECTIVES: To test the hypothesis that PVAC, delipidated, deglycolipidated heat killed Mycobacterium vaccae, is an effective and safe treatment for psoriatic arthritis (PsA). This treatment has shown promising results in psoriasis. METHODS: 36 patients with PsA in two centres were studied in this double blind, placebo controlled, randomised trial. Patients were randomised to receive two intradermal injections of 50 micro g PVAC or placebo and were followed up for 24 weeks. The primary end point was the Psoriatic Arthritis Response Criteria (PsARC), a composite measure based on changes in joint tenderness and swelling scores and physician and patient global assessments. RESULTS: The PsARC response at either 12 or 24 weeks was achieved by 9/18 (50%) placebo and 9/18 (50%) PVAC patients (p = 1.0). No significant differences in the Psoriasis Activity and Severity Index (PASI), patient or physician global assessments, CRP, or Health Assessment Questionnaire score over time were found between the two groups. However, changes in the pain visual analogue scale over time did differ between the two groups (p = 0.006): at 24 weeks the mean score in the PVAC group had declined by 19.2 mm and in the placebo group had increased by 4.8 mm. PVAC was well tolerated with no increased incidence of adverse events compared with placebo. CONCLUSIONS: PVAC was not shown to be as effective as immunotherapy for PsA. The striking response to placebo in this study reinforces the importance of adequately controlling therapeutic trials in PsA.

Adult↗
PubMed2003

Cell death by apoptosis is a feature of the rheumatoid nodule.

OBJECTIVE: To examine the site and extent of apoptosis in the rheumatoid nodule and to determine whether this process make a significant contribution to the control of inflammation in the rheumatoid nodule as in other granulomas. METHODS: Nine nodules and seven synovial membranes were examined by terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) in situ and a subset was further examined by DNA electrophoresis. The phenotype of apoptotic cells was identified using monoclonal antibodies and immunohistology. RESULTS: Apoptosis occurred in all zones of the nodule and, except in one case, was not focused adjacent to the necrotic centre. Apoptosis occurred in 3.5 (4.5)% (mean (SD)) of cells in the nodule and 3.6 (3.1)% of cells in synovial membranes. Apoptosis was more common in nodule T cells (4.1 (2.9)%) than fibroblasts (1.0 (1.4)%), p = 0.01. Among macrophages 3.2 (4.7)% were apoptotic. Banding of DNA consistent with apoptosis was seen in two of three nodules examined. CONCLUSION: Apoptosis occurs at a low level in the nodule, similar to the synovial membrane. The results suggest that two modes of cell death occur in the nodule: apoptosis, which occurs throughout the nodule; and necrosis, which is concentrated near the necrotic centre. Apoptosis was more common in infiltrating inflammatory cells than in resident fibroblasts. These results are consistent with the proposal that apoptosis of infiltrating inflammatory cells is important in controlling accumulation of cells in the rheumatoid nodule as has been established in experimental granulomas.

Adult↗
PubMed2002

Comparison of the faecal microflora of patients with ankylosing spondylitis and controls using molecular methods of analysis.

OBJECTIVES: To determine whether differences within the complex intestinal microflora can be demonstrated between patients with ankylosing spondylitis (AS) and healthy individuals. METHODS: The composition of the faecal microflora of 15 ankylosing spondylitis patients and 15 matched controls was determined using a variety of nucleic acid-based methods, including denaturing gradient gel electrophoresis (DGGE). Concentrations of serum antibodies reactive with intestinal bacteria were determined. T-cell proliferation responses to autologous intestinal bacteria were determined using a bioluminescent assay. RESULTS: DGGE demonstrated a unique and stable bacterial community in the faeces of each individual. No specific differences in colonization profiles were discernible between patients and controls. Analysis of individual bacterial groups using nucleic acid-based methods showed no differences in faecal colonization with Klebsiella pneumoniae or Bacteroides vulgatus. A significantly higher proportion of faecal samples from AS patients were found to contain sulphate-reducing bacteria compared with samples from controls (P=0.0004). Three out of five patients showed elevated T-cell proliferation responses to Bacteroides species cultured from their own faeces. The concentrations of serum immunoglobulin A (IgA) and IgM antibodies reactive with klebsiella or bacteroides cells were lower in the patient group relative to the controls. CONCLUSIONS: By using DGGE, we have demonstrated the complexity and individuality of the human intestinal microflora and shown that this is a confounding factor in determining the possible significance of individual organisms in the pathogenesis of spondyloarthritis. Nevertheless, we demonstrated a higher prevalence of sulphate-reducing bacteria in the faeces of patients with AS. These organisms have been implicated in the pathogenesis of inflammatory bowel disease. We also detected a possible loss of immunological tolerance to autologous Bacteroides isolates in patients with AS.

Bacteroides↗
PubMed2000

Cells expressing dendritic cell markers are present in the rheumatoid nodule.

OBJECTIVE: To determine if dendritic antigen-presenting cells (DC) are present in rheumatoid nodules, as has been reported in the synovial lesions of rheumatoid arthritis. METHODS: Nodules (n = 14) were examined with monoclonal antibodies (Mab) recognizing the DC differentiation/activation markers CD83, CMRF44, and CMRF56 and an antibody recognizing the CD1a antigen present on epithelial tissue associated DC. Results. Cells expressing CMRF44 were common in rheumatoid nodules, comprising 22% of nucleated cells versus 13% in synovial membranes (n = 10). Cells positive for CD1a (5%) and CD83 (2%) were less common. A majority (86%) of CMRF44 positive cells were also positive for the macrophage marker CD14. This left a significant minority of putative DC that were single stained with CMRF44. CONCLUSION: Cells bearing DC markers are as frequent in the rheumatoid nodule as in the synovial lesions. A majority are "indeterminate" cells that are CD14 positive but a proportion are single stained putative DC. The lack of lymphoid collections containing DC and T and B lymphocytes in the nodule suggests that local presentation of antigen may not occur in the rheumatoid nodule, as is thought to be the case in synovial membranes containing lymphoid follicles. This difference could potentially be explained by different states of activation, and differentiation of DC within the 2 lesions.

Adult↗
PubMed1999

Synovial fluid transforming growth factor beta inhibits dendritic cell-T lymphocyte interactions in patients with chronic arthritis.

OBJECTIVE: To examine whether rheumatoid synovial fluid (SF) inhibits dendritic cell (DC) expression of the CD80 and CD86 costimulator molecules and contributes to SF T lymphocyte hyporesponsiveness. METHODS: Cell-free rheumatoid SF was tested for its effect on DC-stimulated autologous/allogeneic mixed lymphocyte reactions and for its effect on DC surface antigen expression, as assessed by flow cytometry. Blocking monoclonal antibodies were used to identify the SF cytokines that inhibited DC-T lymphocyte interactions. RESULTS: Low concentrations of SF (2.5%) could inhibit DC-mediated autologous and allogeneic T lymphocyte proliferation. This inhibitory effect could be reversed by neutralizing transforming growth factor beta (TGFbeta) and interleukin-2 (IL-2), but not by IL-12, in the SF. Hyaluronic acid, IL-6, IL-10, and tumor necrosis factor alpha were not associated with SF inhibition. In vitro culture alone and crosslinking with the CD40 ligand up-regulated DC CD80/CD86 expression and costimulator function, and this was not affected by inclusion of SF. In the presence of SF, DC clustered with autologous T lymphocytes showed decreased CD80 and CD86 expression, and variable CD80/CD86 decreases were observed on DC clustered with allogeneic T lymphocytes. CONCLUSIONS: TGFbeta in SF appears to suppress T lymphocyte function, which may affect both signaling to DC and the induction of DC costimulator function.

Antibodies, Monoclonal↗
PubMed1998

Changing patterns in the use of slow acting antirheumatic drugs for the treatment of rheumatoid arthritis.

AIM: To report on the changing use of slow acting antirheumatic drugs in the treatment of rheumatoid arthritis by contrasting prescribing patterns in 1990 and 1995. METHOD: Data were extracted from the case notes of 103 outpatients with rheumatoid arthritis. Results were compared with those obtained in 1990 in a survey of 81 patients using identical methods. RESULTS: There was a significant increase in the use of methotrexate between 1990 and 1995, and a marked decrease in the use of auranofin. A new feature was the use of drugs in combination. Methotrexate was the most effective agent and auranofin least effective (p = 0.02). The agent with the highest average toxicity score was D-penicillamine. The long term tolerability of methotrexate was superior, with a median time for remaining on therapy 6.4 times longer than that of the other slow acting antirheumatic drugs (p = 0.01). CONCLUSIONS: Our results suggest that identified trends in the altered use of slow acting antirheumatic drugs for treatment of rheumatoid arthritis are rationally based on the increased use of the most effective agents and decreased use of those with greater toxicity and lesser efficacy.

Adult↗
PubMed1998

Pathogenic mechanisms in the rheumatoid nodule: comparison of proinflammatory cytokine production and cell adhesion molecule expression in rheumatoid nodules and synovial membranes from the same patient.

OBJECTIVE: To investigate the production of proinflammatory cytokines and expression of cell adhesion molecules in the rheumatoid nodule. METHODS: Cytokine content (tumor necrosis factor alpha [TNFalpha], interleukin-1beta [IL-1beta], and IL-1 receptor antagonist [IL-1Ra]), at the messenger RNA (mRNA) and protein levels, and cell adhesion molecule expression were studied in 16 rheumatoid nodules and 6 synovial membranes. RESULTS: Macrophages in the rheumatoid nodules contained TNFalpha, IL-1beta, and IL-1Ra mRNA and protein, particularly in perivascular cells of the stroma and in the palisading layer. All cell adhesion molecules studied were expressed in both the rheumatoid nodules and synovial membranes, with increased expression of E-selectin in the rheumatoid nodule compared with the synovial membrane, and with the absence of vascular cell adhesion molecule 1 expression on cells of the palisading layer in the rheumatoid nodule. CONCLUSION: The presence of similar proinflammatory cytokines and cell adhesion molecules in the rheumatoid nodule and synovial membrane suggests that similar pathogenic processes result in the chronic inflammation and tissue destruction in these lesions.

Adult↗
PubMed1998

Chickenpox monoarthritis: demonstration of varicella-zoster virus in joint fluid by polymerase chain reaction.

A case of chickenpox monoarthritis is described. The presence of varicella zoster virus (VZV) within the joint was demonstrated by the detection of viral DNA in synovial fluid at a time when peripheral blood cells were negative. This strongly suggests a direct role of VZV in causing monoarthritis complicating chickenpox. The use of the polymerase chain reaction allows more rapid (2 days) confirmation of the diagnosis. Early enough diagnosis would raise the question of using acyclovir to shorten the duration of arthritis.

Antibodies, Viral↗
PubMed1997

Osteitis--an under-recognised association with seronegative spondyloarthropathy?

AIM: To emphasise osteitis as a feature of the spondyloarthritides. METHOD: We describe four cases spanning a spectrum of the spondyloarthritides in which osteitis was a feature. RESULTS: One patient had psoriatic arthritis with palmar-plantar pustular psoriasis and extensive osteitis involving the tibia and fibula. This case provides a link with two cases with SAPHO syndrome (synovitis, acne, pustulosis hyperostosis, osteitis) who had palmar-plantar pustulosis and osteitis. Many now argue that this syndrome is a form of spondyloarthritis. The fourth case, which was of particular interest to us, had enteric reactive arthritis and scintigraphic changes strongly suggesting the presence of osteitis of individual bones in the wrist. CONCLUSION: We propose that these four cases demonstrate that osteitis may be another feature common to the spondyloarthritides and SAPHO. Awareness of this may facilitate better documentation of this feature of the disease.

Adult↗
PubMed1996

Reactive arthritis: characteristics in southern New Zealand.

AIM: To review the clinical characteristics of patients with reactive arthritis and their associated triggering infections in a New Zealand community. METHOD: We reviewed the records of 60 patients with reactive arthritis. For comparison data was also collected on 30 randomly selected patients with psoriatic arthritis. RESULTS: Reactive arthritis affected a young age group. Half the episodes occurred in the age range 16-24 years and the mean age, (SD) of affected patients was 27(10) years cf psoriatic arthritis 40 (17) years, p<0.001. Almost half had a disease course longer than 2 yr and erosive joint damage in one quarter. Two thirds required treatment with sulphasalazine or methotrexate and patients with reactive arthritis were admitted to hospital frequently: 37% vs psoriatic arthritis 7%, p<0.001. Antecedent diarrhoea was documented in 23 episodes whereas a diagnosis of sexually acquired reactive arthritis was made in 11. CONCLUSION: Reactive arthritis has a significant impact on a young age group in this community. This provides a further reason for action to contain the rapidly increasing prevalence in the community of gastrointestinal infections known to trigger reactive arthritis.

Adolescent↗