Multidrug resistances genes in rheumatology. Is their role immunological or pharmacological?
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ATP Binding Cassette Transporter, Subfamily B, Mem↗
Biomedical subjects
C Jorgensen
Publications and source records attributed to C Jorgensen.
New therapeutic targets in rheumatoid arthritis.
Gene therapy has the significant advantage of providing targeted and continuous administration of a therapeutic agent within the joint. A number of targets of choice are discussed, including cytokines, metalloproteinase inhibitors and angiogenesis costimulators. Gene transfer can also be used to inhibit intracellular biological cascades (apoptosis, signal transduction, cell differentiation). Preliminary Phase I ex vivo studies have confirmed the feasibility of gene therapy in rheumatoid arthritis. Vectors will have to be improved before in vivo studies are performed.
Animals↗
Systemic viral interleukin-10 gene delivery prevents cartilage invasion by human rheumatoid synovial tissue engrafted in SCID mice.
OBJECTIVE: To assess the effects of viral interleukin-10 (vIL-10) gene delivery on human rheumatoid synovial tissue. METHODS: SCID mice were engrafted subcutaneously with human rheumatoid synovial tissue and homologous cartilage before systemic injection of 10(9) plaque-forming units of type 5 E1a Elb-deficient non-replicative adenovirus vector containing the vIL-10 gene under control of the cytomegalovirus promoter (AdvIL-10; n = 10) or a control gene (AdvIL-10mut; n = 7). Three weeks later, the graft was removed for histologic analysis of cartilage invasion by synovial tissue. The number of CD3-positive mononuclear cells was assessed in the synovial tissue by immunohistology. Messenger RNA (mRNA) expression of matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), and proinflammatory cytokines was determined by polymerase chain reaction. RESULTS: Systemic vIL-10 gene transfer resulted in high sustained production of vIL-10 protein in SCID mouse sera (mean +/- SD 25 +/- 5 ng/ml on day 40 post vector injection). Moreover, vIL-10 mRNA expression was detected in the synovial tissue 3 weeks after intravenous injection of AdvIL-10, reflecting the gene transfer in the human graft. In animals treated with AdvIL-10, cartilage invasion by rheumatoid synovial tissue was significantly inhibited compared with the control vector (mean +/- SD histologic score 2.5 +/- 0.52 versus 0.75 +/-0.8; P < 0.0001). The number of T cells infiltrating the synovium and perichondral resorption in the animals treated with AdvIL-10 gene were not significantly modified relative to the control vector. In animals treated with AdvIL-10, the MMP-3-TIMP-1 balance was partially restored, independent of the effect on mRNA expression of tumor necrosis factor a, IL-1, IL-6, or IL-8. CONCLUSION: Systemic vIL-10 gene transfer prevented cartilage invasion by synovial tissue engrafted in SCID mice. This model offers the opportunity to study the biologic effects of gene transfer in vivo in rheumatoid synovium.
Adenoviridae↗
Intracytoplasmic Th1 and Th2 cytokines in rheumatoid arthritis blood and synovial tissue.
In rheumatoid arthritis (RA), T cells have been proposed either as a main actor or as an epiphenomenon in such a primarily synoviocyte-driven disease. A major issue remains the remarkable paradox between the T cell infiltrate and the relative failure to detect definite markers of their activity. To determine the Th1/Th2 cytokine profile in RA synovium, we used a single cell flow cytometric assay for interleukin-2 (IL-2), interferon-gamma (IFN-gamma), IL-4 and IL-10 in paired peripheral blood (PB) and synovial tissue (ST) lymphocytes from RA and osteoarthritis (OA) patients and PB lymphocytes from healthy controls. Cytokines were undetectable in unstimulated PB and ST lymphocytes. More stimulated PB and ST CD4(+)lymphocytes produced IFN-gamma than IL-4, for all individuals tested. RA PB CD4(+)lymphocytes showed the same Th1 cytokine pattern as normal controls. No increase of such a Th1 profile was observed for ST lymphocytes. A specific recruitment of T CD4(+)lymphocytes in the rheumatoid inflamed synovium could not be concluded on the basis of these results.
Adult↗
Effect of tropisetron on vomiting during patient-controlled analgesia in children.
Patient-controlled analgesia (PCA) is associated with a high incidence of vomiting which is distressing and interferes with postoperative recovery. Tropisetron, a long-acting selective 5-HT3 receptor antagonist, has been shown to be effective in preventing nausea and vomiting associated with PCA use in adults and chemotherapy in children. We assessed the efficacy of prophylactic intraoperative administration of tropisetron on the incidence of vomiting in children using morphine PCA. We studied 58 patients, allocated randomly to receive tropisetron 0.1 mg kg-1 to a maximum of 5 mg, or normal saline. Children who received tropisetron had an incidence of vomiting during the first 24 h after operation of 22% compared with 66% in the control group (P = 0.001). In addition, the severity of vomiting was less in the tropisetron group with only one child (4%) vomiting more than twice compared with nine (31%) in the control group (P = 0.01). We conclude that tropisetron is efficacious in reducing the incidence and severity of postoperative vomiting in children using PCA.
Adolescent↗
Immunological evaluation of cytokine and anticytokine immunotherapy in vivo: what have we learnt?
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Antibodies, Monoclonal↗
Acute osteoporotic vertebral collapse: open study on percutaneous injection of acrylic surgical cement in 20 patients.
OBJECTIVE: The aim of this study was to determine the efficacy of percutaneous vertebroplasty in treating painful spinal osteoporotic collapse. SUBJECTS AND METHODS: Twenty-three cases of vertebral collapse were evaluated with CT and MR imaging to determine osteoporotic origin and recent evolution. Percutaneous vertebroplasties were performed using CT guidance. The 20 patients included in the study (17 women, 3 men; 62-92 years old) had acute pain of less than 1 month's duration that hindered ambulation and required treatment with narcotic drugs. They underwent this procedure for analgesic purposes. The analogic visual scale of Huskisson was used for pain when scoring assessment. RESULTS: In 15 patients (75%), pain relief was complete within 24 hr after injection. Analgesic administration was stopped in 14 patients. Mild pain persisted in three (15%) of the remaining five patients. In one other patient (5%), crural pain was observed with cement leakage in the psoas muscle. In the fifth patient (5%), pain recurred after the patient was lifted. The pain was related to a new acute collapse of an adjacent vertebrae. CONCLUSION: Vertebroplasty for the treatment of osteoporotic vertebral collapse is a minimally invasive procedure that provides immediate pain relief and enables the patient to become quickly mobile.
Acrylic Resins↗
Longitudinal determination of antiphospholipid antibodies in lupus patients without previous manifestations of antiphospholipid syndrome. A prospective study.
OBJECTIVE: To investigate whether serial anticardiolipin determination contributes to the clinical management of patients with systemic lupus erythematosus (SLE) with no previous sign of the antiphospholipid syndrome (APS). METHODS: In 90 patients with SLE with no previous clinical manifestations of the APS, repeated clinical evaluations were performed, and serial blood samples (obtained over a 30 month period, range 13-53 mo) were screened for antiphospholipid antibodies (aPL). Anticardiolipin antibodies (aCL) were detected using an ELISA and considered positive if the result was >25 GPL on 2 separate occasions. Patients were not required to be on a specific treatment regimen during the study. RESULTS: Thirty-four patients (37%) had at least one positive ELISA and 11 (11/90, 12%) 2 positive ELISA for IgG aCL during the study. Lupus anticoagulant (LAC) was found in 16 patients, and a false positive VDRL in 5. At study completion, the total number of clinical or laboratory events associated with APS was 30. In univariate analysis, aCL was significantly associated only with LAC (p<0.012). Presence of aCL also correlated with hemoglobin level, anti-DNA antibody, leukocyte count, and the SLE Disease Activity Index (SLEDAI). LAC and aCL were significantly associated with each other (OR 5.17; 95% CI 1.5-17.7), but LAC had a better positive predictive value than aCL for arterial thrombosis and neurological events. CONCLUSION: Among our patients with SLE without previous clinical manifestations of APS, positive aCL did not predict the occurrence of APS within the next 3 years, but was statistically related to the clinical disease activity (SLEDAI).
Adolescent↗
Radiologic progression in early rheumatoid arthritis treated with methotrexate.
OBJECTIVE: To evaluate radiologic progression in patients with early rheumatoid arthritis (RA) receiving methotrexate (MTX) as the first slow acting drug. METHODS: An open, prospective study of 29 patients with RA (21 F, 8 M, mean age 48.5+/-15.4 yrs). The mean duration of RA was 6.6 (2-60) months; and rheumatoid factor was present in 11 cases. Clinical, biological, and radiographic evaluations were done before the start of MTX treatment and after 13+/-3.8 months. Radiographs of hands and wrists were blindly studied by 2 physicians, using Larsen's and modified Sharp's methods. There was a significant correlation for the scores of the 2 physicians evaluated by kappa coefficient. Radiographic evolution was defined as an increase of 15 points in the radiologic score by each method used. RESULTS: Patients showed significant clinical improvement after one year of MTX treatment. Despite clinical and biological improvement, significant mean radiographic progression was noted, with Larsen's method (p = 0.001) and Sharp's method (p = 0.034), without reaching the maximum score. However, using the definition of radiographic progression, the radiologic scores indicated stabilization in 23 patients with Larsen's method and in 24 patients with Sharp's method. CONCLUSION: This study revealed mild radiographic progression in early RA patients treated with MTX for one year. Further controlled studies are needed.
Antirheumatic Agents↗
Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis.
IL-10 is a potent anti-inflammatory cytokine that has received growing attention for its therapeutic potential. We examined the efficiency of adenoviral-mediated gene transfer of IL-10 on the incidence and severity of murine collagen-induced arthritis (CIA). Male DBA1 mice immunized with collagen II were treated by systemic administration of 10(9) plaque-forming units of replication-defective adenoviral vector expressing viral IL-10 (vIL-10) on day 30, when clinical symptoms of arthritis start. The transgene was shown to inhibit the onset of CIA, to decrease severity, and profoundly suppress the overall joint histopathology of the experimental arthritis. Significant IL-10 concentrations were obtained in the serum of injected animals for 7 days. Inhibition of arthritis was enhanced by administration of increasing doses of adenovirus-vIL-10. In addition, the local immunosuppressive effect of gene-delivered vIL-10 could be neutralized by a monoclonal anti-vIL-10 Ab. The CIA symptoms in the group treated with the same construct expressing inactive vIL-10 (vIL-10 mut) were similar to those in untreated animals. Our data indicate that a single systemic administration of an adenoviral vector encoding vIL-10 may be a good candidate to suppress arthritis.
Adenoviridae↗
Gene therapy in osteoarticular diseases: where are we?
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Arthritis, Rheumatoid↗
Mutations of the p53 tumour suppressor gene in erosive rheumatoid synovial tissue.
Erosive rheumatoid arthritis (RA) is accompanied by synovial tissue hyperplasia associated with the proliferation of transformed-appearing synovial lining cells. In the present study we have analysed the expression of the p53 tumour suppressor gene in the synovial pannus tissue from patients at various stages of the disease. We used a combination of polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) on DNA and reverse transcription, PCR and sequencing on cDNAs from synovial tissues or purified synovial cell populations of 24 RA and three osteoarthritis (OA) patients. We also studied p53 expression by immunohistochemical analysis. Mutations suspected after SSCP were identified by systematic sequencing of the p53 exon 6, especially in the fibroblast-like, adherent synovial cell population, associated with an erosive disease. Some accumulation of the protein was detected in immunohistochemical analysis of the p53 tumour suppressor gene in the patients' synovial tissues. However, no sign of malignancy was seen in these patients after a 2-year survey. These results show some abnormalities in the p53 tumour suppressor gene in RA patients, but do not allow this to be related to characteristic proliferative features of the rheumatoid synovium.
Adolescent↗
Interleukin-4 and interleukin-10 are chondroprotective and decrease mononuclear cell recruitment in human rheumatoid synovium in vivo.
We used the severe combined immunodeficient (SCID) mouse model to assess the effect of interleukin-4 (IL-4) or IL-10 injection on cartilage degradation and mononuclear cell (MNC) recruitment to human rheumatoid synovium in vivo. Human rheumatoid synovium and cartilage from five rheumatoid arthritis patients, obtained after joint replacement surgery, were engrafted subcutaneously to 6-8-week-old SCID CB17 mice. Synovial tissues were injected with recombinant human IL-4 (rhIL-4, 100 ng; rhIL-10, 100 ng), both cytokines, or tumour necrosis factor-alpha (TNF-alpha) (1000 U), or phosphate-buffered saline twice a week for 4 weeks. The graft was removed and immunochemical analysis was carried out to assess intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin expression. Moreover, cartilage degradation was assessed through the quantification of the erosion surface on a computerized image of the engrafted cartilage at high power view. MNC recruitment in the synovial tissue was determined by labelling blood MNC with indium-111 before their intraperitoneal injection. The activity obtained in the region of the graft were determined with a gamma camera 72 hr postinjection. The results are expressed as a percentage of initial injected activity. After 4 weeks we observed a decrease of cartilage area in controls (77 +/- 8%), inhibited after injection of IL-4, IL-10, or both cytokines (90 +/- 3%, 89.1 +/- 4%, 89.2 +/- 5% respectively), and 57 +/- 17% after TNF-alpha injection. The % MNC activity in the graft decreased to 77 +/- 81% (NS), 9 +/- 4% (P < 0.003) and 19 +/- 6% (P < 0.007) compared with untreated synovial tissue after treatment with IL-4, IL-10, or both cytokines, respectively. Moreover, IL-10 but not IL-4 decreased the expression of ICAM-1 but not VCAM-1 or E-selectin by synovial cells. These results suggest that IL-10 and IL-4 could have chondroprotective properties, and that IL-10 but not IL-4 inhibits MNC traffic towards the synovial tissue efficiently.
Animals↗
Gastric administration of recombinant 65 kDa heat shock protein delays the severity of type II collagen induced arthritis in mice.
OBJECTIVE: The 65 kDa heat shock protein (HSP) chaperonin is a highly conserved intracellular protein. HSP are involved in the pathogenesis of arthritis, but are not able to induce experimental arthritis. T cell clones recognizing the 180-188 amino acid sequence of 65 kDa HSP are present in inflamed synovium of both adjuvant arthritis and rheumatoid arthritis (RA). Oral administration of bovine collagen II or co-chaperonin 10 kDa HSP has been shown to induce an immune tolerance state to collagen induced arthritis (CIA). We investigate the effect of oral gavage with 65 kDa HSP on CIA. METHODS: We immunized 6-8-week-old DBA1 male mice with bovine type II collagen. A group of 25 mice were given oral recombinant mycobacterial 65 kDa HSP before immunization (30 microg in 200 microl phosphate buffered saline (PBS) at Days -7, -5, -2) while PBS alone was administered in 27 controls. A 3rd group was fed 65 kDa HSP according to the same protocol but was not immunized with collagen II (n = 8). The clinical arthritis score was recorded 3 times/week until Day 60. Antibodies to collagen II were determined by ELISA. RESULTS: The incidence of arthritis was comparable in the 2 groups (72 vs 70%). The onset of arthritis was not delayed in mice fed HSP. However, the severity of arthritis was lower 10 days after arthritis onset in animals fed 65 kDa HSP (clinical score 1.83 +/- 0.79 vs 2.74 +/- 1.1; p < 0.0001). No animals in Group 3 had arthritis. Serum IgG anti-type II collagen levels were decreased in HSP treated mice (optical density 0.33 +/- 0.21 vs 0.46 +/- 0.21; p < 0.0001). However, the ratio of IgG1/IgG2a antitype II collagen antibody response remained unchanged in the mice fed 65 kDa HSP. CONCLUSION: These results suggest that oral administration of 65 kDa HSP may diminish collagen induced arthritis.
Administration, Oral↗
Gene therapy in bone and joint diseases. An update.
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Animals↗
Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an open, retrospective, observational study.
A total of 453 rheumatoid arthritis (RA) patients were followed up for 35.2 +/- 27.9 months (range 3-106). The clinical parameters decreased significantly after 6 months. Twenty-eight patients were in remission (6.4%). Rheumatoid factor (RF) positivity was less common in the group of patients in remission, with a higher frequency of visits and methotrexate (MTX) onset after 65 yr. There was a significant degradation of radiographic lesions (n = 60). A total of 101 patients (23.1%) stopped MTX, for toxicity (n = 61) and failure (n = 20). The onset of MTX after 65 yr, a low number of visits and the occurrence of side-effects were predictive of MTX withdrawal. A total of 259 patients (59.3%) had side-effects. A Ritchie's index < or = 10, a lower polymorphonuclear cell count and the absence of RF were predictive of side-effects. The probability of being on MTX at 5 yr was 73%. This study confirms the high efficacy of MTX in RA.
Adult↗
Study of eight cases of cancer in 426 rheumatoid arthritis patients treated with methotrexate.
OBJECTIVE: To report cancer cases in 426 rheumatoid arthritis patients treated with methotrexate, and determine whether there was an increased incidence of cancer compared with patients never treated with methotrexate (rheumatoid controls) and to the whole regional population. METHODS: The duration of methotrexate treatment was 37.4 (SD 27.9) months. This population was compared with 420 rheumatoid arthritis controls and with a regional population of 812,344 people. Life table analysis was performed to compare the cancer incidence in the two rheumatoid populations. Adjustment for potentially confounding factors was done. The indirect standardisation methods was used to compare each rheumatoid population with the regional population. RESULTS: Eight cases of cancer (1.88%; 4.04 cases/1000 person years) were diagnosed in the methotrexate population v six (1.43%; 58.8 cases/1000 person years) in the rheumatoid controls. The life table method showed a higher incidence of cancer in the rheumatoid controls (P = 0.0001). In a multivariate analysis (Cox model), the only significant factor explaining this difference in the cancer incidence was age (P = 0.02). In the regional population there were 6418 new cases of cancer (0.79%; 2.85 cases/1000 person years). By the indirect standardisation method, the ratio of observed cases to expected cases of cancer in each of the rheumatoid populations was not significantly different from 1. CONCLUSIONS: In these eight cases, methotrexate was not found to be responsible for generating cancers. However, because of data regarding lymphomas and methotrexate, and because of the short follow up, especially in the control group, longer prospective studies are warranted.
Adult↗
Inflammatory joint disease after immunizations. A report of two cases.
Serious adverse effects of immunizations are uncommon. The hepatitis B vaccine has been implicated in a few dozen cases of extraarticular, systemic, or inflammatory joint disorders. We report two cases in which hepatitis A vaccination (Havrix, Smith Kline Beecham) was followed by a connective tissue disorder or a spondylarthropathy in two healthy males aged 50 and 24 years, respectively. Both patients were HLA B27-negative but carried the HLA DR1 and/or DR4 antigen. The outcome was favorable after treatment with a corticosteroid or a nonsteroidal antiinflammatory agent. The pathophysiology of immunization-related rheumatic disorders may involve circulating immune complexes and/or a mechanism similar to that seen in reactive arthritis, i.e., a genetically-determined susceptibility to the bacterial or viral antigens contained in vaccines.
Adult↗