High-resolution free-breathing automated quantitative myocardial perfusion by cardiovascular magnetic resonance for the detection of functionally significant coronary artery disease.

AIMS: Current assessment of myocardial ischaemia from stress perfusion cardiovascular magnetic resonance (SP-CMR) largely relies on visual interpretation. This study investigated the use of high-resolution free-breathing SP-CMR with automated quantitative mapping in the diagnosis of coronary artery disease (CAD). Diagnostic performance was evaluated against invasive coronary angiography (ICA) with fractional flow reserve (FFR) measurement. METHODS AND RESULTS: Seven hundred and three patients were recruited for SP-CMR using the research sequence at 3 Tesla. Of those receiving ICA within 6 months, 80 patients had either FFR measurement or identification of a chronic total occlusion (CTO) with inducible perfusion defects seen on SP-CMR. Myocardial blood flow (MBF) maps were automatically generated in-line on the scanner following image acquisition at hyperaemic stress and rest, allowing myocardial perfusion reserve (MPR) calculation. Seventy-five coronary vessels assessed by FFR and 28 vessels with CTO were evaluated at both segmental and coronary territory level. Coronary territory stress MBF and MPR were reduced in FFR-positive (≤0.80) regions [median stress MBF: 1.74 (0.90-2.17) mL/min/g; MPR: 1.67 (1.10-1.89)] compared with FFR-negative regions [stress MBF: 2.50 (2.15-2.95) mL/min/g; MPR 2.35 (2.06-2.54) P < 0.001 for both]. Stress MBF ≤ 1.94 mL/min/g and MPR ≤ 1.97 accurately detected FFR-positive CAD on a per-vessel basis (area under the curve: 0.85 and 0.96, respectively; P < 0.001 for both). CONCLUSION: A novel scanner-integrated high-resolution free-breathing SP-CMR sequence with automated in-line perfusion mapping is presented which accurately detects functionally significant CAD.

MMP expression in rheumatoid inflammation: the rs11568818 polymorphism is associated with MMP-7 expression at an extra-articular site.

Matrix metalloproteinases (MMPs) contribute to the joint damage in rheumatoid arthritis (RA). Less is known of the involvement of MMPs at extra-articular sites of rheumatoid inflammation. We assessed the relative contribution from MMP-1, MMP-3, MMP-7 and MMP-12 to joint and extra-articular tissue destruction and inflammation by comparing gene expression in joint synovia and subcutaneous rheumatoid nodules from RA patients. Expression of MMP-1 and MMP-3 predominated in synovia, whereas MMP-12 expression was significantly higher in rheumatoid nodules. Markedly higher MMP-7 expression distinguished a subgroup of nodules that featured infiltrating monocyte/macrophage-producing MMP-7 protein. The high MMP-7 expression in nodules was associated with the single-nucleotide polymorphism (SNP) rs11568818 (-181A>G, MMP-7 promoter) and more active inflammation within the nodule lesions. Patients with such nodules had significantly earlier age of RA onset. Our findings indicate that the expression of MMP-1 and MMP-3 occurs relatively independent of the tissue microenvironment with substantial expression also at extra-articular sites. MMP-12 expression reflects the involvement of monocyte/macrophages in rheumatoid inflammation. Evidence for the association between the rs11568818 SNP and increased MMP-7 expression is restricted to nodules, which indicates that consequences of the MMP-7 polymorphism are likely to manifest within aspects of immune/inflammatory activity that are monocyte/macrophage-mediated.

IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis.

The interleukin (IL)-17/IL-23 axis is an important pro-inflammatory pathway in rheumatoid arthritis (RA). IL-23 maintains CD4(+) T-helper 17 (Th(17)) cells, whereas IL-12 negates IL-17A production by promoting Th(1)-cell differentiation. We sought evidence for any effect of polymorphisms within the interleukin-23 receptor (IL-23R), IL-12 or IL-21 genes on serum cytokine concentrations in 81 patients with RA. Serum cytokines were measured using bead-based multiplex assays. Targeted cytokines were detected in up to 66% of samples. A subgroup of 48 patients had detectable serum IL-17A. Within this subgroup, patients, homozygous for the IL-23R rs11209026 major allele had significantly higher serum IL-17A concentrations compared with patients with the minor allele (394.51 ± 529.72 pg ml(-1) vs 176.11 ± 277.32 pg ml(-1); P = 0.017). There was no significant difference in any of the cytokine concentrations examined in patients positive for the minor allele vs homozygosity for the major allele of IL-12B rs3213337, IL-12Bpro rs17860508 and IL-21 rs6822844. Our results suggest the IL-23R Arg381Gln substitution may influence serum IL-17A concentrations. In patients with the 381Gln allele higher IL-23 concentrations may be needed to produce similar IL-17A concentrations to those in patients with the 381Arg allele. This suggests altered IL-23R function in patients with the minor allele and warrants further functional studies.

Evidence for association of an interleukin 23 receptor variant independent of the R381Q variant with rheumatoid arthritis.

OBJECTIVE: The rare allele of a non-synonymous interleukin 23 receptor (IL23R) single nucleotide polymorphism (SNP) rs11209026 (p.Arg381Gln) confers strong protection against Crohn disease (CD) and psoriasis. Other IL23R variants also exhibit association with CD, genetically independent of rs11209026. In rheumatoid arthritis (RA), IL23 is an important determinant of the production of IL17A, a cytokine of consequence in inflammation and bone destruction. While there is no previous support for strong association of IL23R with RA, the possibility of a weaker role for IL23R variants in the aetiology of RA cannot be eliminated. METHODS: A New Zealand RA cohort was tested for association with six IL23R SNPs and the resulting data combined with a reanalysis of the Wellcome Trust Case Control Consortium data and a previously published Spanish data set. The combined data set totals over 3000 Caucasian cases and 3800 controls, which has sufficient power to detect a risk of as low as odds ratio (OR) = 1.2. RESULTS: Our data emphasise the lack of association of rs11209026 with RA (OR 1.01, 95% confidence interval (CI) 0.88 to 1.16, p = 0.86). However there was some evidence for association of rs1343151 with RA (OR 1.14, 95% CI 1.06 to 1.22, p = <0.001). CONCLUSIONS: While requiring further replication, these data further support a role for the IL17A/IL23 pathway in RA. Understanding how different variants of IL23R associate, at varying levels of strength, with contrasting groups of immune-mediated diseases (CD, psoriasis, ankylosing spondylitis, RA) will enhance knowledge on the aetiology of these diseases.

Disease Activity Score 28-ESR bears a similar relationship to treatment decisions across different rheumatologists, but misclassification is too frequent to replace physician judgement.

OBJECTIVES: To determine whether physician factors are associated with disease activity status in RA, independently of 28-joint disease activity score (DAS28)-ESR and to re-evaluate DAS28-ESR misclassification rates for identifying active disease in usual practice. METHODS: A prospective observational study of outpatients with RA seen by 17 rheumatologists across New Zealand. Active disease was defined by an increase in therapy together with a reason of 'active disease'; very low disease activity was defined by a decrease in therapy together with a reason of 'patient well'. The independent physician effect was assessed using logistic regression. Sensitivity and specificity of current DAS28-ESR thresholds were calculated. RESULTS: In 511 patients, 178 had active disease, 220 had low disease activity, 37 had very low disease activity and 76 had uncertain disease activity status. There was no independent effect of physician upon active disease status (P = 0.16) with DAS28-ESR [(OR) 3.7] explaining around 50% of the variability in active disease status. There was a trend towards an independent effect of physician upon very low disease activity status (P = 0.06) and greater variability in the distribution of DAS28-ESR for patients in very low disease activity. DAS28-ESR thresholds showed a significant risk of misclassification for active disease. CONCLUSIONS: DAS28-ESR discriminates satisfactorily between groups of patients with active and non-active disease, with no evidence of additional physician-specific factors to explain disease activity status. However, DAS28-ESR is not as good for discriminating remission from non-remission status. There are appreciable probabilities of misclassification error, which make DAS28-ESR inappropriate as a sole guide for treatment decisions.

Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis.

OBJECTIVE: There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 (CCL3L1) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by beta-chemokines is a feature of autoimmunity, and that the CCR5Delta32 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1 copy-number influences susceptibility to RA and type 1 diabetes (T1D). METHODS: We measured CCL3L1 copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian. RESULTS: A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08-1.66, p = 0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75-1.60, p = 0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98-2.20, p = 0.064) and in the combined RA/T1D cohort (OR 1.30, 95% CI 1.00-1.54, p = 0.003). Genetic interaction between CCL3L1 dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1 copy-number was ablated by a dysfunctional CCR5 (CCR5Delta32). CONCLUSIONS: These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5Delta32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.

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.

Rationale for a trial of immunosuppressive therapy in acute schizophrenia.

Schizophrenia is a debilitating, costly, socially disruptive, life-threatening disease in which available treatments are largely palliative and empirical, and produce significant short- and long-term side effects. Therefore, a strong case can made for exploring alternative treatments with a rational basis for use in this disease. Considerable evidence indicates that autoimmune processes may be involved in some forms of schizophrenia, including altered risk of certain autoimmune diseases in patients and their relatives, shared epidemiological features, and apparent involvement of genes known to influence the immune response repertoire. Attempts to provide direct evidence for autoimmune processes have proven elusive, possibly due to the technical difficulty inherent in accessing autoantibodies with high affinity for brain cell-surface receptors. In view of this impasse, we argue for a well-designed trial in schizophrenia of immunosuppressive therapy, which is now the mainstay of therapy for many autoimmune diseases. Analysis of disease states in which immunosuppression has been effectively used over many decades provides guidelines necessary for a meaningful trial.

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.

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.

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.

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.

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.

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.

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.

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.

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.