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1.  Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(8):992-999.
Objectives
To characterise the phenotype of the putative dendritic cells strongly expressing Jak3 and STAT4, which have been previously identified in the synovial tissue of patients with active rheumatoid arthritis (RA).
Methods
Synovial biopsy specimens were obtained at arthroscopy from 30 patients with active RA (42 synovial biopsies). Immunohistological analysis was performed using monoclonal antibodies to detect dendritic cell subsets, including activation markers and cytokines relevant to dendritic cell function. Co‐localisation of cell surface markers and cytokines was assessed primarily using sequential sections, with results confirmed by dual immunohistochemistry and immunofluorescence with confocal microscopy.
Results
The dendritic cells identified in RA synovial tissue that strongly express Jak3 also strongly express STAT4 and STAT 6 and are correlated with the presence of serum rheumatoid factor. These cells are not confined to a single dendritic cell subset, with cells having phenotypes consistent with both myeloid‐ and plasmacytoid‐type dendritic cells. The activation status of these dendritic cells suggests that they are maturing or mature dendritic cells. These dendritic cells produce IL12 as well as interferon α and γ.
Conclusions
The close correlation of these dendritic cells with the presence of serum rheumatoid factor, a prognostic factor for worse disease outcome, and the strong expression by these cells of components of the Jak/STAT transcription factor pathway suggest a potential therapeutic target for the treatment of RA.
doi:10.1136/ard.2006.060822
PMCID: PMC1954703  PMID: 17223651
rheumatoid arthritis; myeloid dendritic cells; plasmacytoid dendritic cells; IL12; interferon alpha; interferon gamma
2.  Changes in synovial tissue Jak‐STAT expression in rheumatoid arthritis in response to successful DMARD treatment 
Annals of the Rheumatic Diseases  2006;65(12):1558-1564.
Background
Modulation of Jak‐STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis (IA).
Objective
To examine the effect of successful disease‐modifying antirheumatic drug (DMARD) treatment on the expression of Jak‐STAT in a cohort of patients with active rheumatoid arthritis.
Methods
Synovial tissue biopsy specimens from 16 patients with active rheumatoid arthritis, taken before and after initiation of DMARD treatment, were examined for the presence of janus kinase (Jak)3, signal transducer and activator of transcription (STAT)1, STAT4 and STAT6 expression using immunohistochemistry.
Results
Successful treatment with DMARDs results in reduction in STAT1 expression in the lining, and STAT1 and STAT6 in the sublining of rheumatoid arthritis synovial tissue. Although the overall expression of STAT4 and Jak3 was not significantly altered by DMARD treatment, there was a significant reduction in the expression of the STAT4 and Jak3 bright cells, thought to be an activated dendritic cell subpopulation.
Conclusion
Results show that Jak3, STAT1, STAT4 expression and STAT6 sublining expression decrease in response to successful treatment of rheumatoid arthritis with standard DMARDs. Therefore, altering the expression of these pathways may represent an alternative treatment option, either through promoting up‐regulation of inhibitory pathways, or suppressing inflammatory paths.
doi:10.1136/ard.2005.050385
PMCID: PMC1798468  PMID: 16760256
3.  Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis 
Annals of the Rheumatic Diseases  2005;65(2):149-156.
Background
Modulation of Jak‐STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis.
Objective
To document Jak‐STAT expression in a cohort of patients with active rheumatoid arthritis (RA), spondyloarthritis (SpA), and osteoarthritis (OA) and compare these subsets with normal synovial tissue.
Methods
Synovial tissue biopsy specimens from patients with RA, OA, and SpA and histologically normal tissue (n = 10 in each arthritis group) were examined for the presence of Jak3, STAT1, STAT4, and STAT6 expression using immunohistochemistry. Phenotyping was performed using immunohistochemistry and immunofluorescence. Clinical and serological characteristics of patients with RA expressing Jak3‐STAT4 were assessed.
Results
STAT1, STAT4, and Jak3 protein expression was generally increased in inflammatory arthritis. In contrast, STAT6 expression was relatively heterogeneous. A subpopulation of CD1a positive dendritic cells unique to seropositive patients with RA was detected. These cells showed intense protein expression for Jak3, STAT4, and STAT6.
Conclusion
CD1a positive dendritic cells intensely express Jak3, STAT4, and STAT6 in seropositive RA tissue and may be an alternative marker for dendritic cells in their early stages of activation as well as providing a tool for identifying RA at the level of the synovium. Jak3 inhibition may be a potential therapeutic target to prevent dendritic cell maturation in RA. STAT1 expression is increased in inflammatory arthritis, suggesting that its pro‐apoptotic and anti‐inflammatory effects cannot effectively counteract inflammation. STAT6 expression is heterogeneous in synovium, suggesting a possible homoeostatic role in addition to any anti‐inflammatory effects.
doi:10.1136/ard.2005.037929
PMCID: PMC1798020  PMID: 16096332
dendritic cells; rheumatoid arthritis; transcription factors
4.  Illness behaviour in patients with arthritis. 
Annals of the Rheumatic Diseases  1995;54(4):245-250.
OBJECTIVES--To determine if there are specific patterns of illness behaviour in patients with arthritis, and if abnormal patterns of illness behaviour are associated with withdrawal from trials of anti-inflammatory drugs, and to examine which aspects of illness behaviour are perceived by rheumatologist to be related to the disease process. METHODS--The illness behaviour questionnaire (IBQ) was administered to 211 patients with rheumatoid arthritis (RA) and 107 patients with osteoarthritis (OA) participating in five drug trials of NSAIDs at the beginning of the studies, and was commented upon by 17 clinical rheumatologists. RESULTS--Factor analysis of 211 patients with RA produced a unique factor solution. RA patients were more preoccupied with their illness and its effects and worried more about their health than patients with OA. Patients who withdrew from drug trials showed behaviour patterns similar to those of chronic pain patients, and different from those of patients who completed the studies. When asked to account for a rheumatoid patient's response to the IBQ, rheumatologists focused on physical symptoms and did not recognise some of the psychological issues which patients saw as being relevant. CONCLUSIONS--We have demonstrated differences in illness behaviour between patients with OA and with RA. Patients withdrawing from drug trials of NSAIDs showed differences in illness behaviour compared with those successfully completing the trials. Rheumatologists underestimated the impact of the disease on their RA patients' psychological well being.
PMCID: PMC1005568  PMID: 7763099
5.  Phenotypic and genotypic analysis of mononuclear cells from patients with Felty's syndrome. 
Annals of the Rheumatic Diseases  1990;49(2):103-106.
Phenotypic and genotypic characteristics of the peripheral blood mononuclear cells in nine patients with Felty's syndrome have been examined. One patient had an increased number and percentage of peripheral blood mononuclear cells with the phenotype CD3+ Leu-7+ CD16+ and showed a clonal rearrangement of the T cell receptor B chain gene. The remaining eight patients all showed a germline configuration of the T cell receptor B chain gene. In two patients an increased proportion of CD3+ Leu-7+ CD16- peripheral blood mononuclear cells (45 (SD 11)% of peripheral blood mononuclear cells) were found, while the remaining six patients had proportions of CD3+ Leu-7+ cells similar to those of patients with uncomplicated rheumatoid arthritis. These data confirm that patients with Felty's syndrome are heterogeneous, with at least three different peripheral blood mononuclear cell phenotypic subsets. One subset is characterised by a clonal expansion of an unusual lymphocyte subpopulation, another by polyclonal expansion, and the third subset has the same proportions of peripheral blood mononuclear cells as patients with uncomplicated rheumatoid arthritis.
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PMCID: PMC1003987  PMID: 2317110
6.  Autoantibodies in patients with juvenile chronic arthritis and their immediate family relatives. 
Annals of the Rheumatic Diseases  1990;49(12):968-972.
Antibodies to nuclear antigens were assessed in 23 children with juvenile chronic arthritis (JCA) and 66 of their first degree relatives. Serum samples from 16 patients with JCA (70%) and nine relatives (14%) had antinuclear antibodies by indirect immunofluorescence. Antibodies against nuclear antigens in rabbit thymus extract or an erythroblastoid cell line (K562) were detected by countercurrent immunoelectrophoresis and immunoblotting in 16 patients (70%) and 39 family relatives (59%). Immunoblotting did not show any banding patterns common to all patients with JCA, though bands in the 43-45 kD range were detected in 5/23 patients. Anticardiolipin antibodies were found in 7/23 patients. In total, 18/20 families (90%) had members other than the probands with detectable autoantibodies. In five families immunoblotting showed common banding patterns between the probands and other members. This suggests that there might be an inherited trend towards autoimmune responses in some families of patients with JCA.
PMCID: PMC1004288  PMID: 2270968
7.  Hepatic methotrexate content and progression of hepatic fibrosis: preliminary findings. 
Annals of the Rheumatic Diseases  1991;50(7):477-480.
Liver tissue from 16 patients with rheumatoid arthritis was studied. The patients had received low dose methotrexate weekly for a minimum of 12 months between two liver biopsies. The progression of pericellular fibrosis was measured by computerised image analysis. Extracts of these liver biopsy specimens were pooled into five samples according to the progression of hepatic fibrosis and analysed by high performance liquid chromatography. The concentrations of methotrexate, 2,4 diamino-N(10)-methylpteroic acid, and methotrexate polyglutamate were markedly increased in the samples obtained from the three patients who recorded the greatest increase in fibrosis. These preliminary data suggest that progression of hepatic fibrosis is related to the retention of methotrexate and metabolites in the liver.
PMCID: PMC1004461  PMID: 1715157
8.  Two methods of assessment of methotrexate hepatotoxicity in patients with rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1991;50(7):471-476.
Serial liver biopsy specimens from 18 patients with rheumatoid arthritis receiving a weekly dose of methotrexate 7.5-20 mg for a minimum of 12 months were assessed semiquantitatively and by a microcomputer image analysis system. The semiquantitative histological method showed a significant increase in pericellular collagen and in overall disease while morphometry showed a significant increase in pericellular, perivenular, and portal tract collagen. There was a significant correlation between the two methods, but morphometry had the advantage of objectivity and efficiency. There was no correlation between the increase in collagen and the accumulated dose of methotrexate, which suggests that other factors in addition to methotrexate may contribute to liver injury.
Images
PMCID: PMC1004460  PMID: 1877853
9.  Does steroid pulsing influence the efficacy and toxicity of chrysotherapy? A double blind, placebo controlled study. 
Annals of the Rheumatic Diseases  1990;49(6):370-372.
To test the hypothesis that early steroid pulsing augments the efficacy and decreases the toxicity of chrysotherapy 40 patients with rheumatoid arthritis were studied in a double blind, placebo controlled study. During the first three months of gold treatment group 1 received monthly intravenous methylprednisolone pulsing (steroid group) while group 2 received placebo (placebo group). All patients were assessed clinically and serologically over a 24 week period. Twelve patients were withdrawn before completion of the study and all but one of the remaining 28 patients reported clinical and serological improvements. Two patients in the steroid group were withdrawn owing to gold induced side effects while four were withdrawn in the placebo group. These small numbers were not significantly different. Minor side effects occurred more commonly in the placebo group. The clinical response was clearly better in the steroid group with statistical significance almost being achieved. In an endeavour to obtain a significant conclusion further patients will now be entered into this study.
PMCID: PMC1004102  PMID: 2116773
11.  D-penicillamine withdrawal in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1984;43(2):213-217.
Thirty-eight patients with rheumatoid arthritis in remission on penicillamine were entered into a prospective, randomised, placebo controlled study to determine the effects of gradual penicillamine withdrawal, to find a serological marker capable of predicting relapse, and to assess the effects of reintroduction of penicillamine. 80% of patients attempting gradual penicillamine withdrawal flared. There was no single serological marker capable of predicting outcome consistently. Decreasing SH levels were highly specific for recurrence of active synovitis but were insensitive. Reintroduction of penicillamine was successful. The implications of these findings, particularly concerning duration of therapy with disease modifying drugs, are discussed.
PMCID: PMC1001467  PMID: 6370151
12.  Ankylosing spondylitis and adenocarcinoma of the lung 
Annals of the Rheumatic Diseases  1982;41(3):292-294.
A man with long standing and severe ankylosing spondylitis, treated with radiotherapy, developed a primary adenocarcinoma of the lung in an area of apical fibrosis. The significance of this is discussed and the literature reviewed.
Images
PMCID: PMC1000931  PMID: 7092344
13.  Effects of chrysotherapy on circulating lymphocyte numbers and subsets. 
In a prospective 24 week study of 25 patients with rheumatoid arthritis (RA) weekly intramuscular (IM) sodium aurothiomalate resulted in a small but significant reduction in the circulating lymphocyte count. Analysis of absolute levels of pan T cells, T4 helper cells, T8 suppressor cells, T4/8 ratio, B cells, and major histocompatibility complex (MHC) class II positive cells showed reductions in these subsets, though these changes did not reach significance. At entry there was no association between circulating lymphocyte counts and subsets and clinical and laboratory indices which reflected disease activity, and during the study gold responders could not be differentiated from non-responders with regard to changes in lymphocyte counts and subsets. Thus this study suggests that weekly IM gold leads to a modest reduction in circulating lymphocyte numbers which involves most subsets. This effect appears to be independent of the clinical efficacy of this drug.
PMCID: PMC1003436  PMID: 3125797
15.  Low molecular weight IgM in juvenile chronic arthritis. 
Archives of Disease in Childhood  1988;63(12):1453-1456.
Low molecular weight IgM, the monomeric subunit of pentameric IgM, was clearly detected by immunoblotting and filtration chromatographic techniques in six patients with juvenile chronic arthritis and in trace quantities in a further eight of 24 patients studied. This low molecular weight IgM moiety contributed up to 33% of the total circulating IgM and was strongly associated with raised serum concentrations of IgM and the presence of antinuclear antibodies, extractable antinuclear antibodies, and rheumatoid factor. Immunoblot analysis of positive serum samples showed small quantities of other low molecular weight oligomers of IgM in addition to monomeric IgM. It is postulated that the presence of low molecular weight IgM in the serum of patients with juvenile chronic arthritis reflects a disorder of the intracellular assembly of IgM subunits during a stimulated IgM immune response. The pathogenetic role of low molecular weight IgM remains uncertain.
PMCID: PMC1779214  PMID: 3266068
16.  Studies on the interaction of rheumatoid factor with monosodium urate crystals and case report of coexistent tophaceous gout and rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1985;44(6):384-389.
Gout and classical rheumatoid arthritis rarely coexist. We report a patient with strong evidence for both these diseases. Possible reasons for the negative correlation between these diseases are summarised. One hypothesis suggests inhibition of surface activity of monosodium urate crystals (MSU) by binding of rheumatoid factor (RF). This was studied with a purified monoclonal rheumatoid factor (mRF) with specificity for IgG. The mRF bound preferentially to MSU coated with IgG in contrast with the IgM control. Inhibition of the neutrophil chemiluminescence (CL) response to IgG-coated MSU was observed at concentrations of mRF that had no effect on the CL response to uncoated crystals. Neutrophil activation was not altered by coating crystals with an IgM control at the same concentration. These data suggest that RF may bind to antigenic determinants on exposed Fc of adsorbed IgG and block the interaction of crystal-bound IgG with Fc receptors. Although crystal coating by RF may modify the expression of gouty arthritis, it is unlikely to be the sole explanation for the dissociation between gout and RA.
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PMCID: PMC1001657  PMID: 4015200
17.  Impaired delayed type cutaneous hypersensitivity in rheumatoid arthritis reversed by chrysotherapy. 
Annals of the Rheumatic Diseases  1989;48(2):108-113.
A prospective 24 week study of 31 patients with active rheumatoid arthritis (18 women, 13 men) was undertaken to determine whether weekly intramuscular sodium aurothiomalate (gold) would influence delayed type cutaneous hypersensitivity (DTH) and other indices of cell mediated immunity. DTH to seven recall antigens was measured by Multitest on three occasions during the study. Twenty five patients completed the study. At entry 13 patients (12 female) were anergic, and no significant correlations were found between DTH and other clinical and immunological indices. Women showed a significantly greater depression of DTH than men. At week 24 only three of the patients were anergic with significant increase in mean DTH score being noted particularly to tuberculin, candida, and streptococcus. Improvement in DTH was observed in both gold responders and non-responders. In conclusion, patients with active rheumatoid arthritis show impairment of DTH, which is reversed by chrysotherapy. This effect is most apparent in women and appears to be relatively independent of the clinical response.
PMCID: PMC1003694  PMID: 2494956
18.  Pulse steroid therapy in rheumatoid arthritis: can equivalent doses of oral prednisolone give similar clinical results to intravenous methylprednisolone? 
Pulse methylprednisolone therapy has dramatic effects on clinical and immunological parameters of disease activity in patients with rheumatoid arthritis. Previous studies of this treatment have all used the intravenous route and methylprednisolone succinate. This study addresses the question of whether oral prednisolone in equivalent doses can substitute for intravenous methylprednisolone in pulse therapy in a double blind parallel study. It is shown that oral prednisolone has clinical and immunological effects equivalent to those of intravenous methylprednisolone, making it possible to administer pulse therapy to patients with rheumatoid arthritis as outpatients without the inconvenience and inherent dangers of intravenous administration.
PMCID: PMC1003439  PMID: 3278694
19.  Fatal subcutaneous aspergillosis following necrotizing fasciitis: a case report. 
Skin or subcutaneous infection with aspergillus is uncommon. It has been described in disseminated aspergillosis, as localized infection in the immunocompromised host and as a complication of trauma and burns. Described in this paper is a diabetic patient who developed a fatal Aspergillus infection following debridement of a necrotizing fasciitis. "Fruiting bodies," rarely found in vivo, were seen on pathologic examination of subcutaneous tissue. Her course was similar to that of burn patients with invasive fungal disease, where mortality is high and radical debridement is the only chance for cure.
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PMCID: PMC2589255  PMID: 2356626
20.  Infectious complications associated with renal transplantation: an analysis of risk factors. 
To assess the multiple risk factors reported to be associated with onset of serious bacterial, fungal, viral, and protozoal infections in renal allograft recipients, a retrospective study of all renal transplantations performed at Yale-New Haven Medical Center from the inception of the transplantation program in December, 1967, to December, 1975, was undertaken. Ninety-six renal allograft transplants in 85 patients were available for evaluation during this study period. Renal allograft recipients were evaluated for incidence of infection from time of transplantation until transplant nephrectomy, death, or January 1, 1976. All infections were characterized by type of infection, organism, site, and time of onset post-transplantation. Recipients with infections were also evaluated for their donor type, living-related or cadaveric, age at time of transplantation, granulocytopenia, corticosteroid therapy, and rejection episodes. There were 215 infections, 92 of which were defined as serious, in 78 of the 96 renal allograft recipients. Eighteen renal allograft recipients had no infections. Granulocytopenia, but not rejection, correlated with serious infections at some time in the patient's course. However, no significant temporal relationship between serious infections and episodes of granulocytopenia or rejection could be established. Mortality rate and incidence of serious infection was higher in the group receiving high dose corticosteroid therapy compared with the group receiving lower doses of corticosteroids. The mortality rate in these 85 transplant recipients was 33%. Seventy-four percent of these deaths were directly related to infection (24% of 85 patients).
PMCID: PMC2595686  PMID: 373266

Results 1-20 (20)