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ID PMID Title PublicationDate abstract
10233853 Sustained elevated levels of VCAM-1 in cultured fibroblast-like synoviocytes can be achiev 1999 Apr Rheumatoid arthritis is characterized by hyperplasia of the synovial lining and invasion of cartilage and bone by a subset of resident synovial cells named fibroblast-like synoviocytes. They are characterized by elevated expression of the vascular cell adhesion molecule-1 (VCAM-1). The intensity of VCAM-1 expression correlates with the degree of inflammation of the synovial joint. Differential VCAM-1 expression may determine inflammatory cell accumulation through its interaction with leukocytes that express the counterreceptor integrins alpha4beta1 and alpha4beta7. Elevated levels of VCAM-1 expression are thought to be a consequence of the presence of inflammatory mediators, in particular IL-1beta and TNF-alpha. Fibroblast-like synoviocytes rapidly up-regulate VCAM-1 expression in response to IL-1beta and TNF-alpha, but also to IL-4. However, we now show that the response to IL-1beta or TNF-alpha is of a brief transient nature, even when applied continuously over a period of 12 days, whereas the response to IL-4 or IL-13 is sustained. Great synergy is obtained by combining either IL-4 or IL-13 with TNF-alpha, which results in a highly elevated but also sustained expression of VCAM-1. The mechanism by which IL-4 or IL-13 prolongs VCAM-1 expression can be explained by a dramatic increase in the half-life of VCAM-1 mRNA.
10501685 [Ulcerative stomatitis as clinical clue to inadvertent methotrexate overdose]. 1999 Sep Gastrointestinal side effects and the development of toxic liver fibrosis are well-known side effects of low dose methotrexate therapy. A female patient receiving a long term low dose methotrexate therapy for a seronegative chronic polyarthritis developed an ulcerative stomatitis, as clinical clue to an inadvertently given methotrexate overdose. A summary of other side effects of methotrexate and of oral side effects of other cytostatic agents and immunosuppressive drugs is given.
10695730 The importance of being receptive. 1999 Dec Neuroendocrine system and immune system can communicate via the use of soluble mediators like hormones, neurotransmitters and cytokines. The level of mediators secreted by either of these systems creates the milieu in which immune and neuroendocrine responses take place. For adequate communication between the systems, receptors for hormones, neurotransmitters and cytokines are required. This review describes the role of regulated expression and function of receptors for hormones and neurotransmitters within the immune system in neuroendocrine-immune communication.
10084695 A novel 26 kilodalton antigen expressed on the surface membrane of activated T cells. 1999 Feb We have identified and characterized the tissue distribution of the antigen recognized by a novel monoclonal antibody (mAb) 1B10, raised against an activated gammadelta T cell clone. Immunohistochemistry of tissue sections, and analysis of single cell suspensions by flow cytometry revealed that mAb 1B10 weakly reacted with <6% of normal human peripheral blood mononuclear cells (PBMC). After 5-6 days of in vitro culture of PBMC activated with phytohemagglutinin (PHA), 55% of the CD4+ and 25% of the CD8+ T cells became 1B10+. 1B10 expression was maintained on long term cultured interleukin 2 (IL-2)-dependent T cell receptor (TCR) alphabeta+ and gammadelta+ clones, and importantly, in contrast to resting T cells, the majority of in vivo activated synovial T lymphocytes from a patient with rheumatoid arthritis were 1B10+. In addition, myelo-monocytic U927 cells, tissue macrophages and some epithelia and fibroblasts were found to react with mAb 1B10. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of molecules immuno-precipitated by mAb 1B10 from radio-iodinated cell surface membrane lysates of T lymphocyte and U937 cells revealed 26 and 29 kiloDalton (kDa) glycoproteins respectively. In conclusion, mAb 1B10 recognizes a novel <> appearing 26 kDa T cell activation antigen that may be useful for further studies of activated T cells in health and disease.
9640131 Rheumatoid synovial endothelial cells secrete decreased levels of tissue inhibitor of MMP 1998 Mar OBJECTIVES: Angiogenesis (the formation of new blood vessels) is a major component of the inflammatory pannus in rheumatoid arthritis (RA). Matrix metalloproteinase (MMP) secretion by microvascular endothelial cells is an essential step in angiogenesis. The secretion of MMP1, MMP2, MMP9, and TIMP1 by human microvascular endothelial cells derived from RA synovium (RASE) to normal synovium (NSE) and neonatal foreskin (FSE) was compared. METHODS: Confluent monolayers of endothelial cells in basal medium were pre-incubated for 24 hours in the presence or absence of phorbol myristate acetate (PMA, 100 ng/ml). MMP1 activity was measured using a spectrophotometric assay and western blotting. MMP2 and MMP9 were measured using zymography. TIMP1 was measured by enzyme linked immunosorbent assay and western blotting. RESULTS: There was little difference between the amounts of MMP2 secreted by any of the cell lines. In response to PMA both synovial cell types showed a significantly higher MMP1 and MMP9 activity compared with FSE, although there was no difference between RASE and NSE. Tumour necrosis factor alpha had minimal effect on MMP activity. There was a striking decrease in the amount of TIMP1 secreted by RASE compared with normal synovium. CONCLUSIONS: As overall MMP activity is a balance between the amount of MMP and TIMP1 present, the low levels of TIMP1 produced by RASE would shift the balance in favour of increased MMP activity by these cells. This is likely to contribute to the angiogenic potential of RASE.
11263645 The use of structural allograft for uncontained defects in revision total knee arthroplast 2001 Mar BACKGROUND: To our knowledge, the medium to long-term outcome after revision knee arthroplasty with structural allograft augmentation for reconstruction of uncontained defects has not been determined. The purpose of the present study was to assess the outcome for patients managed with such a procedure. METHODS: We prospectively followed fifty patients who had fifty-two revision knee replacements with sixty-six structural grafts performed at three institutions. Twenty-nine knees (twenty-seven patients) were independently evaluated at a mean of 96.9 months (range, sixty to 189 months) by an investigator who had not been involved in the index procedure. Twelve knees (23%) had a repeat revision at a mean of 70.7 months (range, twenty-six to 157 months). The allograft was retained in two of these patients. Eleven patients died at a mean of ninety-three months (range, sixty-one to 128 months) after the procedure; the structural allograft and implants were intact, and the patients were not awaiting revision at the time of death. RESULTS: Clinical evaluation revealed that the mean modified Hospital for Special Surgery knee score had improved from 32.5 points preoperatively to 75.6 points at the time of the review and the mean range of motion had increased from 60.5 degrees preoperatively to 88.6 degrees. Failure was defined as an increase of less than 20 points in the modified Hospital for Special Surgery knee score at the time of the review or the need for an additional operation related to the allograft. Thirteen knee replacements failed, yielding a 75% success rate. Five knees had graft resorption, resulting in implant loosening. Four knee replacements failed because of infection, and two knees had nonunion between the host bone and the allograft. Two knees (one patient) did not have a 20-point improvement in the knee score. The survival rate of the allografts was 72% (95% confidence interval, 69% to 75%) at ten years. On radiographic analysis, none of the surviving grafts had severe resorption, one had moderate resorption, and two had mild resorption. One knee had a loose tibial component, and three knees had nonprogressive tibial radiolucent lines. All four knees were asymptomatic. CONCLUSIONS: Our results demonstrate that allografts used in revision knee replacement in patients with the difficult problem of massive bone loss have an encouraging medium-term rate of survival.
10088767 Detection of human retrovirus 5 in patients with arthritis and systemic lupus erythematosu 1999 Mar OBJECTIVE: To examine whether human retrovirus 5 (HRV-5) infection is associated with autoimmune rheumatic disease. METHODS: DNA from patients with various disorders including inflammatory diseases and from normal subjects was tested by nested polymerase chain reaction (PCR) for HRV-5 proviral DNA. Positive results were confirmed by DNA sequencing. RESULTS: HRV-5 proviral DNA was detected in 53% of synovial samples from arthritic joints, in 12% of blood samples from patients with rheumatoid arthritis (RA), and in 16% of blood samples from patients with systemic lupus erythematosus. In contrast, it was not detectable by PCR of affected tissues from patients with several other autoimmune diseases and was found in only 1 of >200 tissue specimens obtained at autopsy from non-RA patients. Sequence analysis of the amplified viral segment showed genetic variation between samples with maintenance of the open reading frame, typical of a replicating infectious retrovirus. CONCLUSION: This is the first report of the frequent detection of HRV-5 in any disease. We propose that the possible involvement of HRV-5 in autoimmune and rheumatic disease should be investigated further.
10728440 Antibodies to neuroblastoma cells in rheumatoid arthritis: a potential marker for neuropat 2000 Jan OBJECTIVE: To investigate the prevalence of antibodies to neuroblastoma cells in patients with rheumatoid arthritis (RA) complicated by peripheral neuropathy (PN), and to determine whether there is any relationship of these antibodies with the severity of neuropathy. METHODS: The study was carried out on 28 patients with RA complicated by PN, 29 RA patients without PN and 28 healthy volunteers (HV). A cell-based ELISA method was used to test sera for the presence of IgG and IgM anti-neuroblastoma cell antibodies. Localisation and characterisation of neuroblastoma antigens recognised by patients' sera was carried out by immunofluorescent microscopy and Western blotting. RESULTS: Elevated levels of IgG anti-neuroblastoma cell antibodies were found in 10 (36%) neuropathic patients and in 1 (3%) RA control (chi 2 = 9.53, P = 0.002), while significant levels of IgM anti-neuroblastoma cell antibodies were demonstrated in 10 (36%) neuropathic patients and in 2 (7%) RA controls (chi 2 = 7.12, P = 0.008). Overall, the levels of antibodies in healthy volunteers were significantly lower than in RA controls and patients with PN. No significant relationship was found between the level of anti-neuroblastoma cell antibodies and severity of RA or neuropathy. Immunofluorescence staining of neuroblastoma cells with sera from 18 neuropathic patients demonstrated cytoplasmic and/or nuclear patterns. Western blotting demonstrated reactivity with a heterogeneous group of neuroblastoma antigens. Little or no reactivity was seen with RA control or HV sera. CONCLUSION: Antibodies against neuroblastoma cells are more prevalent in RA patients with peripheral neuropathy than in RA patients without peripheral nerve involvement. Such antibodies may be useful diagnostic markers for peripheral neuropathy in RA.
9402859 Tissue-derived macromolecules and markers of inflammation in serum in early rheumatoid art 1997 Nov We have previously shown that serum concentrations of cartilage oligomeric matrix protein (COMP) are increased early in rheumatoid arthritis (RA) patients who subsequently develop advanced large-joint destruction. A prognostic value for joint damage of serum concentrations of hyaluronan (HA) is also suggested by previous studies. In contrast, serum concentrations of bone sialoprotein (BSP) have not been useful for identifying patients with progressive large-joint destruction. In the present study, we have examined the hypothesis that serum concentrations of these tissue-derived markers are of prognostic value in RA for the development of radiographically detectable joint damage in hands and feet. Serum concentrations of COMP, HA and BSP were quantified in samples obtained from 62 patients within the first year after onset of RA and were related to the development of radiographically detectable damage in these joints after 5 yr. Neither the serum concentrations of COMP nor of BSP at inclusion predicted joint damage in hands and feet after 5 yr, and the concentration of these proteins did not change over the 5 yr period. However, the serum concentration of HA at inclusion correlated with the radiographic score at the 5 yr follow-up (r = 0.425, P < 0.01), but was not a better predictor in this respect than the erythrocyte sedimentation rate or C-reactive protein levels at inclusion. Thus, serum concentrations of the three studied tissue-derived macromolecules were in this study not useful for identifying patients prone to small-joint destruction.
9194209 Antibody responses to gut bacteria in ankylosing spondylitis, rheumatoid arthritis, Crohn' 1997 Specific immunoreactive anti-Klebsiella antibodies are found in patients with ankylosing spondylitis (AS), a significant proportion of whom have occult inflammatory bowel disease. Molecular mimicry between Klebsiella or other bacterial antigens and HLA-B27 has been suggested in the pathogenesis of AS. The specificity of increased immunoreactivity against Klebsiella remains to be assessed against the abundant anaerobic bacterial flora, present either in healthy controls or in patients with ulcerative colitis (UC) and Crohn's disease (CD). Total immunoglobulin (Ig; IgG, IgA, IgM) immunoreactivity was measured by ELISA against Klebsiella pneumoniae, Proteus mirabilis, Escherichia coli and ten anaerobic isolates of the predominant normal bowel flora in 35 patients with active AS, 60 patients with inflammatory bowel disease (30 CD, 30 UC), 60 patients with active rheumatoid arthritis (RA) and 60 healthy controls. Ig immunoreactivity to K. pneumoniae was significantly elevated in AS (P < 0.001), CD (P < 0.001) and UC (P < 0.001) patients compared with RA patients and healthy controls. Furthermore, Ig immunoreactivity to P. mirabilis was significantly elevated only in RA patients, compared with the other inflammatory groups (P < 0.001) and controls (P < 0.001). There was no significant antibody response against E. coli or the ten obligate anaerobes in any of the test groups. The data suggested an increased immune response to Klebsiella in patients with AS, UC, CD and to Proteus in patients with RA. The specificity of these responses in some patients supported a possible role for enteric Klebsiella in the pathogenesis of AS and Proteus in RA. The role of Klebsiella in inflammatory bowel disease requires further study.
11762947 Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory a 2001 Dec OBJECTIVE: To review the occurrence of neurologic events suggestive of demyelination during anti-tumor necrosis factor alpha (anti-TNFalpha) therapy for inflammatory arthritides. METHODS: The Adverse Events Reporting System of the Food and Drug Administration (FDA) was queried following a report of a patient with refractory rheumatoid arthritis who developed confusion and difficulty with walking after receiving etanercept for 4 months. RESULTS: Nineteen patients with similar neurologic events were identified from the FDA database, 17 following etanercept administration and 2 following infliximab administration for inflammatory arthritis. All neurologic events were temporally related to anti-TNFalpha therapy, with partial or complete resolution on discontinuation. One patient exhibited a positive rechallenge phenomenon. CONCLUSION: Further surveillance and studies are required to better define risk factors for and frequency of adverse events and their relationship to anti-TNFalpha therapies. Until more long-term safety data are available, consideration should be given to avoiding anti-TNFalpha therapy in patients with preexisting multiple sclerosis and to discontinuing anti-TNFalpha therapy immediately when new neurologic signs and symptoms occur, pending an appropriate evaluation.
9613344 Antisense oligonucleotides targeting c-fos mRNA inhibit rheumatoid synovial fibroblast pro 1998 Feb OBJECTIVE: To determine whether antisense oligonucleotides targeting c-fos mRNA have the ability to inhibit the growth of interleukin 1 (IL1) stimulated fibroblast-like cells from the synovium in rheumatoid arthritis (RA). METHODS: Fibroblast-like cells established from RA synovium were stimulated by IL1 with antisense or sense oligonucleotides complementary to c-fos mRNA, and the proliferation of these cells was determined by 3H-thymidine incorporation. Effect of antisense oligonucleotides on expression of activator protein 1 (AP1) activity was evaluated using electrophoretic mobility shift assay. RESULTS: C-fos antisense oligonucleotides inhibited IL1 stimulated synovial fibroblast proliferation. The expression of AP1 activity induced by IL1 was suppressed by treatment with antisense oligonucleotides. CONCLUSION: These results suggest the feasibility of antisense strategies designed to suppress c-fos expression as therapeutic agents for RA.
11443200 Involvement of prostaglandin E(2) in interleukin-1alpha-induced parathyroid hormone-relate 2001 Jul Synovial fibroblasts, established in culture from patients with RA, were treated with proinflammatory cytokines and prostaglandin E(2) (PGE(2)) for 24 h. These cells enhanced the production and the messenger RNA expression of PTH-related peptide (PTHrP) using proinflammatory cytokines, such as interleukin (IL)-1alpha, tumor necrosis factor-alpha without the coordination of other cytokines. In addition, PGE(2) which has been induced with IL-1, also enhanced the production of PTHrP. The IL-1alpha-induced PTHrP production was inhibited by PG H synthetase (Cox) inhibitors, indomethacin, and also by Cox-2 inhibitor, NS398. The synovial fibroblasts expressed PGE(2) receptor subtypes, EP2, EP3, EP4, but not EP1, as detected by RT-PCR. Of the PGE(2) receptor agonists, EP4 agonist showed the most marked induction of PTHrP, and EP2 agonist partly induced the production. However, these PGE(2) receptors were not induced by the treatment with IL-1alpha and PGE(2). These results suggest that induction of PGE(2) by IL-1alpha may be an important component of the PTHrP production of the inflammatory process in synovial tissues from patients with RA. These findings are the first to demonstrate that PGE(2) stimulates PTHrP production, which is mediated mostly by EP2 and EP4 receptors.
10736104 Evidence that human immunoglobulin M rheumatoid factors can Be derived from the natural au 2000 Apr The question of whether immunoglobulin (Ig)M rheumatoid factors (RF) arise as the result of an abnormal expansion of already existing clones producing natural autoantibodies or emerge as new clones that are somatically mutated owing to an antigen driven immune response has never been conclusively answered. In this study, an inhibition ELISA was utilized to measure the affinities of recombinant antibodies using VH segments reverted back to their closest germline counterparts (germline revertants). In all cases, the somatically mutated parental RFs had a decreased affinity for immunoglobulin (Ig)G Fc compared to the germline revertant, indicating that the antibodies in the germline configuration had the higher affinities. This demonstrates that somatic mutation is not a prerequisite to generate disease associated antibodies. The presence of mutations in the parental IgM RFS suggests that these cells had been involved in a germinal centre reaction. As the germinal centre is the conventional site of the acquisition of mutations during an antigen driven response, these data suggest a role for germinal centres in the generation of the antibody diversity in addition to the selection of higher affinity antibodies. Assuming that only antigen selected cells survive deletion, these data support the hypothesis that IgM RFS can be derived from the natural autoantibody repertoire and result from an antigen driven response. Mechanisms controlling the survival of B cells based on the affinity/avidity of the immunoglobulin receptor are shown to be functional in patients with rheumatoid arthritis.
10327913 Schizophrenia and the HLA-DRB1 gene in the Japanese population. 1999 May OBJECTIVE: Small Japanese studies have suggested that patients with schizophrenia have higher rates of the HLA-DR1 gene than normal subjects. The authors' goal in the present study was to confirm this finding in a larger number of Japanese subjects. They also investigated the rate of DR4 in Japanese patients with schizophrenia because it has been reported that Caucasian patients with schizophrenia have higher rates of DR4. METHOD: They studied the occurrence of the HLA-DRB1 gene in 233 unrelated Japanese patients with schizophrenia compared with the occurrence of the gene in a group of 493 healthy Japanese volunteers. RESULTS: A larger proportion of the patients with schizophrenia (15.9%) than the comparison subjects (10.5%) were found to have DR1 (DRB1*0101). The proportion of patients (36.9%) and comparison subjects (40.6%) with DR4 did not differ significantly. CONCLUSIONS: Consistent with the findings of three other Japanese studies, the findings of the present study suggest that the rate of HLA-DR1 may be higher in Japanese patients with schizophrenia than in normal Japanese subjects. No evidence for an association between schizophrenia and the rate of DR4 was obtained in this study, although the combined data from the present study and other Japanese studies support the finding of lower rates of DR4 among patients with schizophrenia.
9502421 Constitutive transcription of the human interleukin-6 gene by rheumatoid synoviocytes: spo 1998 Mar The involvement of IL-6 in the pathogenesis of rheumatoid arthritis (RA) has been recently demonstrated. In the present study, we investigated the cellular and molecular mechanisms involved in the spontaneous IL-6 production by the fibroblast-like synoviocytes (FLSs) obtained from patients with RA. Cloned FLSs were established from the bulk cultures of FLSs by the limiting dilution method. Some FLS clones spontaneously produced large amounts of IL-6, whereas others produced low amounts of it. Neither anti-human TNF-alpha nor IL-1 antibody affected spontaneous IL-6 production of these FLS clones, suggesting that IL-6 production of the FLSs was endogenously up-regulated. A luciferase reporter plasmid containing the human IL-6 promoter region was significantly transcribed when transfected into the IL-6 high-producing clones, indicating that the rheumatoid FLSs retained constitutive transcriptional activity of the IL-6 gene. Electrophoretic mobility shift assays revealed that the binding activity of p50 and p65 NF-kappaB subunits and CBF1 was significantly enhanced in the IL-6 high-producing clones compared with that of IL-6 low-producing clones and cultured sarcoma cells, suggesting that spontaneous activation of NF-kappaB and CBF1 may lead to the constitutive transcription of the IL-6 gene by rheumatoid FLSs.
9175933 Rheumatoid arthritis: autoreactive T cells recognising a novel 68k autoantigen. 1997 May OBJECTIVE: A 68k autoantigen has been identified by specific antibodies from patients with rheumatoid arthritis (RA). This study considered whether or not this antigen is a target for T cells and thus may play a part in T cell mediated immunopathology of active RA. METHODS: The 68k antigen was isolated and used in a nitrocellulose bound form to stimulate T cells. Proliferation of T lymphocytes of peripheral blood as well as synovial fluid was measured. RESULTS: Peripheral blood T cells specifically proliferating against the 68k antigen were detected in 19 of 27 patients with RA (70%). For T cells isolated from peripheral blood, proliferation peaked on day 10. When T cells were isolated from actively inflamed synovial fluid, the proliferation kinetics shifted to a peak on day 3. Blockade of HLA class II antigens resulted in an increase of proliferation in the case of HLA-DP. Applying HLA-DP specific antibodies capable of inhibiting antigen presentation mediated by this molecule, T cells of 17 of 27 RA patients (63%) proliferated to a higher extent than with the 68k antigen alone. The phenomenon that an increased proliferation occurred upon blockade of a particular HLA class II family member was also demonstrated for DQ and DR: the 68k antigen likewise stimulated T cells restricted for DP or DQ, respectively. CONCLUSIONS: The novel 68k antigen is a target of both T and B cellular immune responses and as such could play a part in the immune dysfunction of RA. The finding that blocking of certain HLA class II molecules functioning in antigen presentation (for example, via HLA-DQ) results in a higher instead of lower proliferation in vitro, may argue for the presence of antigen specific suppressive T cells.
11023674 Serum levels of ifn-inducible PROTEIN-10 relating to the activity of systemic lupus erythe 2000 Oct IFN-inducible protein-10 (IP-10) is supposed to act as a specific chemoattractant for Th(1)cells. Since Th(1)cells and IFN-gamma are shown to be important for developing systemic lupus erythematosus (SLE), we examined the relationship between serum IP-10 levels and the disease activity. Serum IP-10 levels were markedly increased in the SLE patients depending on the level of disease activity, whereas not in the patients with rheumatoid arthritis (RA). On the other hand, serum MCP-1 levels were increased to a similar extent both in RA and inactive SLE patients, and a little more elevated in active SLE patients. Serum IP-10 levels in SLE patients correlated positively and negatively with levels of anti-DNA antibody and complements, respectively, whereas MCP-1 levels correlated less or not at all. These results suggest that serum IP-10 levels could be a good indicator for the activity of SLE and that IP-10 could play an important immunological role in SLE.
11583481 Lack of pharmacokinetic interaction between rofecoxib and methotrexate in rheumatoid arthr 2001 Oct Rofecoxib is a highly selective and potent inhibitor of cyclooxgenase-2 (COX-2). Methotrexate is a disease-modifying agent with a narrow therapeutic index frequently prescribed for the management of rheumatoid arthritis. The objective of this study was to investigate the influence of clinical doses of rofecoxib on the pharmacokinetics of methotrexate in patients with rheumatoid arthritis. This was a randomized, double-blind, placebo-controlled study in 25 rheumatoid arthritis patients on stable doses of methotrexate. Patients received oral methotrexate (7.5 to 20 mg) on days -1, 7, 14, and 21. Nineteen patients received rofecoxib 12.5, 25, and 50 mg once daily on days 1 to 7, 8 to 14, and 15 to 21, respectively. Six patients received placebo on days 1 to 21 only to maintain a double-blinded design for assessment of adverse experiences. Plasma and urine samples were analyzed for methotrexate and its major although inactive metabolite, 7-hydroxymethotrexate. The AUC(0-infinity) geometric mean ratios (GMR) and their 90% confidence intervals (90% CI) (rofecoxib + methotrexate/methotrexate alone) for day 7/day -1, day 14/day -1, and day 21/day -1, for rofecoxib 12.5, 25, and 50 mg, were 1.03 (0.93, 1.14), 1.02 (0.92, 1.12), and 1.06 (0.96, 1.17), respectively (p > 0.2 for all comparisons to day -1). All AUC(0-infinity), GMR and Cmax GMR 90% CIs fell within the predefined comparability limits of (0.80, 1.25). Similar results were observed for renal clearance of methotrexate and 7-hydroxymethotrexate at the highest dose of rofecoxib tested (50 mg). It was concluded that rofecoxib at doses of 12.5, 25, and 50 mg once daily has no effect on the plasma concentrations or renal clearance (tested at the highest dose of rofecoxib) of methotrexate in rheumatoid arthritis patients.
11453808 Clinical, histological, and immunophenotypic characteristics of injection site reactions a 2001 Jul OBJECTIVE: To study injection site reactions (ISRs) associated with etanercept therapy. DESIGN: Retrospective chart review, along with prospective analysis of selected patients experiencing ISRs associated with etanercept therapy. SETTING: Academic rheumatology/immunology unit and dermatology clinic. SUBJECTS: Patients with rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory seronegative arthritis, psoriatic arthritis, psoriasis, or inflammatory bowel disease. INTERVENTIONS: Skin biopsy specimens were taken from selected patients experiencing ISRs. MAIN OUTCOME MEASURES: Incidence of IRSs and histological and immunophenotypic analysis of ISRs in 3 patients undergoing prospective study. RESULTS: Twenty-one (20%) of 103 of all patients receiving etanercept reported ISRs, all within the first 2 months of inception of therapy. The reactions occurred 1 to 2 days after the last injection and resolved within a few days. Moreover, eventual waning of reactions was observed, with none proving to be dose limiting. Histological examination of all biopsy specimens showed an inflammatory infiltrate composed of predominantly lymphoid cells and some eosinophils, in a perivascular cuffing pattern, without evidence of leukocytoclastic vasculitis. The infiltrating lymphoid cells were predominantly activated mature (HLA-DR(+)/CD3(+)/CD4(-)/CD8(+)) cytotoxic T lymphocytes, with a small number of CD4(+) cells. A biopsy specimen from a recall ISR showed strong HLA-DR expression by epidermal keratinocytes. CONCLUSIONS: Injection site reactions associated with etanercept therapy are common, and may be an example of a T-lymphocyte-mediated delayed-type hypersensitivity reaction, with waning over time due to eventual induction of tolerance.