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ID PMID Title PublicationDate abstract
12661109 [A case of brain ischemia presenting spectacular shrinking deficit in adult-onset Still's 2002 Jul A 63-year-old man presenting remittent fever and multiple arthralgia was diagnosed as adult-onset Still's disease (AOSD), and started with prednisolone treatment. However, he suddenly developed loss of consciousness, paresis of the right upper extremity and aphasia shortly after the treatment. We detected an increased signal of brain tissue lactate at the branch territory of left middle cerebral artery by MR spectroscopy (MRS), but no lesions by diffusion-weighted nor T2-weighted MRI, suggesting acute brain ischemia of embolic mechanism. Most of the symptoms resolved in a couple of hours after the onset, showing spectacular shrinking deficit (SSD). The patient also revealed complication of antiphospholipid antibody syndrome (APS), which may be associated with ischemic event. This is the first case of acute brain ischemia with SSD, which occurred in AOSD with APS. MRS was superior to diffusion MRI in detection of acute brain ischemia.
12399722 [The phenol red thread first results for the assessment of the cut-off value in ocular sic 2002 Sep PURPOSE: To determine the cut-off value of the phenol red-impregnated thread test (Zone-Quick((R)), Menicon trade mark ) for the diagnosis of ocular sicca syndrome using the ROC (receiver operating characteristic) procedure and to estimate the agreement with the Schirmer I test (without anesthetics). MATERIAL: and methods: Fifty-four consecutive patients (including 50 females) with dry eyes, presumably related to an immune disorder, were recruited on the basis of subjective ocular symptoms and medical history (sicca syndrome). Both the phenol red thread (PRT) test and the Schirmer I test (testing periods, 15s and 5min, respectively) were performed in both eyes in random order. Only the lowest result for each test was used in statistical analyses. The same procedure was applied to 29 normal volunteers (no subjective symptoms). The patient and the control groups were matched for age and gender (mean age, 58.1 and 59.6, respectively). RESULTS: The ROC procedure showed that a cut-off value of 12mm in the PRT test provided the best ratio between sensitivity and specificity (56% and 69%, respectively) for the detection of dry eyes. Using this threshold, the agreement with the Schirmer I test was highly significant (kappa test; P<10(-3)). However, discordant results were observed in 32% of subjects. CONCLUSION: Giving a cut-off value at 12mm, the sensitivity and specificity of the PRT are 56% and 69%, respectively. Even if the agreement with the Schirmer I test is highly significant, 32% of patients have discordant results. These two methods of functional assessment of tear secretion are therefore complementary and further studies remain necessary to better understand the place of both tests in clinical practice.
15173640 [Treating severe dry eye syndromes with autologous serum]. 2004 Apr BACKGROUND: Dry eye syndrome with tear deficiency can be improved with artificial tears, which can be associated with topical anti-inflammatory agents. Autologous serum can provide the ocular surface with beneficial growth factors and vitamins. PATIENTS AND METHODS: Twenty-one patients suffering from severe dry eye due to Sjögren's syndrome were treated with 20% autologous serum for 2 Months. The Schirmer I test, break-up time, and fluorescein and lissamine green stainings were performed before and after treatment. Subjective complaints such as burning, foreign body sensation, dryness and photophobia were assessed by a questionnaire as well as a face score reflecting the current condition of patients' eyes. RESULTS: Lissamine green and fluorescein scores improved significantly as well as subjective symptoms of burning, foreign body sensation and dryness (p<0.05). The face score was significantly improved. Bacterial culture of serum delivered to the patients all remained negative. DISCUSSION: Autologous serum provides growth factors and vitamins that are useful for an altered ocular surface due to Sjögren's disease. However, some problems still remain: risk of contamination, arbitrary dilution of autologous serum, and a current lack of regulations for use of autologous serum. A close collaboration between ophthalmologists and the Etablissement Français du Sang (French Blood Bank) is mandatory because autologous serum should be considered as a useful tool to treat severe ocular surface disorders. CONCLUSION: The use of autologous serum improved symptoms and objective signs caused by severe Sjögren's syndrome. Currently, a lack of clear regulations prevents its widespread use in severe ocular surface disorders.
12613883 Understanding dry eye syndrome. 2002 It was my great pleasure to have had the opportunity to give the conference address in addition to being honored by the Professor Dohlman Award. I am proud of the progress in the understanding of dry eye that has been made over the past couple of decades. However, the clinical application of the knowledge that has accumulated lies in the future. Thus far no effective medication has ever been developed for the treatment of severe dry eye. Cyclosoporine may become the first eyedrops to be used, and a series of new drugs containing androgens, immunomodulators, secretagogues, P2Y2 receptor agonists, and others may follow. I believe that medication for the treatment of dry eye will be developed in the not to distant future, and I hope that at the 4th conference in a few years time, we will be able to share these new treatments for the management of dry eye patients.
15505773 Septic arthritis in the adult caused by Streptococcus pneumoniae: a report of 4 cases and 2004 Oct OBJECTIVES: To identify coexistent diseases, clinical features, approaches to management, and predictors of outcome in patients with pneumococcal septic arthritis. METHODS: Case series of 4 adults with Streptococcus pneumoniae septic arthritis seen at a university hospital, plus a review of 115 adults with pneumococcal septic arthritis reported in the medical literature from 1973 through 2003. RESULTS: Among our 4 patients, 3 had polyarticular infections, joint prostheses were involved in 1, 3 had underlying joint diseases, and 1 had concurrent meningitis. Infection was caused by penicillin-intermediate/cephalosporine-susceptible S pneumoniae in 1 patient and penicillin-resistant/cephalosporine-intermediate S. pneumoniae in 1 patient. After a mean treatment duration of 6 weeks, all patients were clinically cured of infection. Review of the literature identified 115 cases of S pneumoniae septic arthritis in adults. Clinical data were available for 107 patients. Twenty-nine cases were polyarticular (26%), joint prostheses were involved in 15 patients (13%), and 61 patients had underlying joint disease (57%). Meningitis was a concurrent infection in 15 cases. The presumed primary focus of infection was the respiratory tree in 44 patients. Ninety-six percent of cases were caused by penicillin-susceptible organisms. Cure of infection with survival was achieved in 83% (79 of 95) of patients with native joint septic arthritis and in 67% (8 of 12) of patients with prosthetic joint infection. A good functional outcome (full range of motion or return to baseline range of motion) after infection was achieved by 44 of 71 patients (62%) with native joint infection and by 4 of 7 patients (57%) with infections of prosthetic joints. The likelihood of cure of infection or good functional outcome was not influenced by method of joint drainage. CONCLUSIONS: S pneumoniae is an uncommon, but not rare, cause of septic arthritis in the adult. Many patients have underlying joint disease (especially rheumatoid arthritis) and coexistent alcoholism. Although most infections involve native joints, prosthetic joint infections comprise 13% of cases. Polyarticular disease occurs in approximately one quarter of patients. Most patients have a preceding or concurrent extra-articular focus of pneumococcal infection. To date, the majority of reported infections are caused by penicillin-susceptible organisms, so penicillin G or a third-generation cephalosporine such as ceftriaxone remains the appropriate treatment option. However, infection with drug-resistant organisms is likely to be an increasing problem in the future. With directed antimicrobial therapy and appropriate joint drainage, the outcome is generally good for patients with native joint infections. In contrast, only two thirds of patients with infections of prosthetic joints survive their infections. Approximately 40% of surviving patients experience functional impairment or chronic pain as a sequelae of their infection.
15188371 Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: 2004 Jun OBJECTIVE: Current treatment options for psoriatic arthritis (PsA) are limited. Leflunomide, an oral pyrimidine synthesis inhibitor, is highly effective in the treatment of rheumatoid arthritis, and small studies have suggested similar efficacy in PsA. We undertook this double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of leflunomide in patients with PsA and psoriasis. METHODS: One hundred ninety patients with active PsA and psoriasis (at least 3% skin involvement) were randomized to receive leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally) or placebo for 24 weeks. The primary efficacy end point was the proportion of patients classified as responders by the Psoriatic Arthritis Response Criteria (PsARC). Additional efficacy (joint and skin involvement), safety, and quality-of-life assessments were performed. RESULTS: At 24 weeks, 56 of 95 leflunomide-treated patients (58.9%; 95% confidence interval [95% CI] 48.4-68.9) and 27 of 91 placebo-treated patients (29.7% [95% CI 20.6-40.2]) were classified as responders by the PsARC (P < 0.0001). Significant differences in favor of leflunomide were also observed in the proportions of patients achieving modified American College of Rheumatology 20% improvement criteria, improvement in the designated psoriasis target lesion, and mean changes from baseline in Psoriasis Area and Severity Index scores and quality-of-life assessments. Diarrhea and alanine aminotransferase increases occurred at higher rates in the leflunomide group. No cases of serious liver toxicity were observed. CONCLUSION: Leflunomide is an effective treatment for PsA and psoriasis, providing a safe and convenient alternative to current therapies.
12487726 Decreased activity of hepatic P-glycoprotein in the isolated perfused liver of the adjuvan 2002 Nov 1. We investigated the hepatobiliary transport of doxorubicin in the isolated perfused liver prepared from the adjuvant arthritis rat, an animal model for rheumatoid arthritis, to examine the hepatic P-glycoprotein activity in the adjuvant arthritis rat. 2. Liver was isolated from the normal and the adjuvant arthritis rat and perfused for 60 min with recirculating buffer and the perfusate and bile samples were collected at timed interval. 3. The elimination of doxorubicin in the adjuvant arthritis rat tended to be reduced, but it was not significantly different from the normal rat. Biliary clearance (CL(bile)) in the normal rat was 1.93 +/- 0.48 ml min(-1), whereas, CL(bile) in the adjuvant arthritis rat was significantly decreased to 0.40 +/- 0.13 ml min(-1). 4. CL(bile) was markedly decreased to about 0.15 ml min(-1) in the presence of 100 microM verapamil in both types of rat. Methotrexate treatment had no effect on CL(bile) in both the normal and adjuvant arthritis rat (2.18 +/- 0.22 and 0.47 +/- 0.22 ml min(-1), respectively). 5. The results suggest that the hepatic P-glycoprotein activity was markedly decreased in the adjuvant arthritis rat and the effect of methotrexate on the hepatic P-glycoprotein activity did not corresponded to its anti-inflammatory effect.
15514108 Hypervariable genes--experimental error or hidden dynamics. 2004 Oct 28 In a homogeneous group of samples, not all genes of high variability stem from experimental errors in microarray experiments. These expression variations can be attributed to many factors including natural biological oscillations or metabolic processes. The behavior of these genes can tease out important clues about naturally occurring dynamic processes in the organism or experimental system under study. We developed a statistical procedure for the selection of genes with high variability denoted hypervariable (HV) genes. After the exclusion of low expressed genes and a stabilizing log-transformation, the majority of genes have comparable residual variability. Based on an F-test, HV genes are selected as having a statistically significant difference from the majority of variability stabilized genes measured by the 'reference group'. A novel F-test clustering technique, further noted as 'F-means clustering', groups HV genes with similar variability patterns, presumably from their participation in a common dynamic biological process. F-means clustering establishes, for the first time, groups of co-expressed HV genes and is illustrated with microarray data from patients with juvenile rheumatoid arthritis and healthy controls.
12563696 Inhibition of disease progression by a novel retinoid antagonist in animal models of arthr 2003 Feb OBJECTIVE: To investigate the usefulness of a novel retinoic acid receptor (RAR) antagonist (BMS-189453) in animal models of arthritis. METHODS: BMS-189453 was tested in HIG-82 rabbit synovial fibroblasts to determine its ability to repress collagenase (matrix metalloproteinase-1, MMP-1) mRNA expression in vitro. Cells were stimulated with phorbol myristate acetate or interleukin 1 beta and mRNA quantified by slot-blot analysis. In vivo, BMS-189453 was evaluated in 2 animal models of arthritis: collagen induced arthritis (CIA) in mice and streptococcal cell wall induced arthritis (SCWA) in rats. Clinical scores for arthritis were recorded weekly. At the end of each study, limbs were evaluated histologically. In CIA, these results were correlated with mRNA levels for collagenase-3 (MMP-13) and stromelysin-1 (MMP-3) as determined by Northern blot. RESULTS: BMS-189453 reduced MMP-1 expression in HIG-82 synovial fibroblasts in culture. BMS-189453 treatment blocked the clinical progression of arthritis beyond soft tissue inflammation in the CIA model. In the SCWA model, BMS-189453 treatment resulted in significantly reduced swelling with no notable progression to joint distortion/destruction. Histological evaluation of the joints from animals in both models confirmed this result. Analysis of mRNA from the CIA paws showed that BMS-189453 prevented the overexpression of MMP-13 and MMP-3 in arthritic joints. CONCLUSION: Improvement in clinical and histologic variables in 2 separate animal models, along with simultaneous reduction in MMP expression in the affected joint, suggests that RAR antagonists such as BMS-189453 may be useful as agents to treat rheumatoid arthritis and for determining the role of MMP in disease progression. This is the first study to show the clinical potential of RAR antagonists in arthritis.
15049603 [Psoriatic rheumatism]. 2004 Jan 15 Five to 7% of patients with cutaneous psoriasis suffer from inflammatory rheumatism that is sero-negative for rheumatoid factor, and is often erosive. The inflammation is predominant to the entheses and can affect the axial or peripheral skeleton, often in an associated manner. The most common peripheral signs are those of an asymmetrical oligo-arthritis type, and the most evocative are arthritis of the distal inter-phalangeal joints. A symmetrical polyarthritis can also be observed. The severe mutilating forms are fortunately very rare. Axial signs include sacro-iliitis that is more often bilateral and spinal involvement of an ankylosing spondyloarthitic type, predominating in the cervical and thoracic spine. The treatment usually calls for a non-steroidal anti-inflammatory and local injection of cortisone. Steroids must be used with care and reserved for the severe forms. DMARDS include Salazopyrin, methotrexate, and in the severe and resistant forms, the inhibitors of TNFalpha.
12794840 Sex effect on clinical and immunologic quantitative trait loci in a murine model of rheuma 2003 Jun OBJECTIVE: To explore the effect of sex on clinical and immunologic traits in major histocompatibility complex-matched (H-2d) F(2) hybrid mice with proteoglycan (PG)-induced arthritis and to identify how the quantitative trait locus (QTL) on the X chromosome influences the onset QTL of another chromosome. METHODS: (BALB/c x DBA/2)F(2) hybrid mice were immunized with cartilage PG, and a genome-wide linkage analysis was performed using >200 simple sequence-length polymorphic markers. The major clinical traits (susceptibility, onset, and severity) were assessed, and PG-specific T and B cell responses, and the production of proinflammatory and antiinflammatory cytokines (tumor necrosis factor alpha, interleukin-1 [IL-1], IL-6, interferon-gamma, IL-4, IL-10, and IL-12) were measured in 133 arthritic and 426 nonarthritic female and male F(2) hybrid mice. The major clinical and immunologic traits were linked to genetic loci, and potential linkages among these QTLs and the effect of sex were analyzed. RESULTS: Thirteen QTLs reported in previous studies were confirmed. Binary traits (susceptibility to arthritis) and disease onset were female specific and were identified on chromosomes 3, 7, 10, 11, 13, and X. QTLs for disease severity were mostly male specific and were located on chromosomes 1, 4, 5, 8, 14, 15, and 19. In addition, we identified 4 new QTLs for the onset of arthritis on chromosomes 3, 4, and 11, and 1 new QTL for severity on chromosome 14; all showed a strong gender association. A locus on the X chromosome interacted with a QTL on chromosome 10, and these 2 loci together seemed to control disease incidence and onset. Most of the clinical traits (QTLs) shared common regions with the immunologic traits and frequently showed a locus-locus interaction. CONCLUSION: Numerous immunologic QTLs overlap with clinical QTLs, thus providing information about possible mechanisms underlying QTL function. Disease susceptibility and onset showed predominant linkage with the female sex, under the control of a QTL on the X chromosome, while the severity QTLs were more strongly linked to the male sex.
14636180 The inhibition of inducible nitric oxide synthase reverts arthritic-induced decrease in pi 2003 Dec Experimental arthritis induced by Freund-adjuvant administration is a model of chronic inflammation and rheumatoid arthritis associated with a decrease in pituitary growth hormone (GH) and hepatic insulin-like growth factor I (IGF-I) gene expression. Excessive nitric oxide (NO) synthesis by inducible NO synthase (iNOS) has been implicated in the pathogenesis of inflammatory illness. Moreover, NO participates in the regulation of GH secretion at both the hypothalamus and the pituitary. We have examined the role of iNOS activation in producing the changes in the GH-IGF-I axis in arthritic rats. Adult male Wistar rats received aminoguanidine or vehicle from day 20, after adjuvant or vehicle injection, until day 28. Two hours and 30 min after the last aminoguanidine injection, all rats were killed by decapitation. Arthritis increased hypothalamic expression of somatostatin mRNA while it decreased pituitary GH mRNA expression, and both effects were prevented by aminoguanidine administration. In arthritic rats, the parallel decrease in serum IGF-I, and in hepatic IGF-I content and mRNA expression, correlates with the decrease in circulating GH concentrations. Aminoguanidine administration to arthritic rats did not modify either serum GH or serum IGF-I concentrations, or hepatic IGF-I mRNA expression. However, aminoguanidine administration to control rats resulted in a decrease in serum GH concentrations and in a decrease in both hepatic IGF-I mRNA expression and serum IGF-I concentrations. These data suggest that NO mediates the arthritis-induced decrease in GH mRNA expression by acting at a hypothalamic level, but it is not involved in the decrease in hepatic IGF-I mRNA expression.
12368214 Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced a 2002 Oct Rheumatoid arthritis is characterized by progressive synovial inflammation and joint destruction. While matrix metalloproteinases (MMPs) are implicated in the erosion of unmineralized cartilage, bone destruction involves osteoclasts, the specialized cells that resorb calcified bone matrix. RANK ligand (RANKL) expressed by stromal cells and T cells, and its cognate receptor, RANK, were identified as a critical ligand-receptor pair for osteoclast differentiation and survival. A decoy receptor for RANKL, osteoprotegerin, (OPG) impinges on this system and regulates osteoclast numbers and activity. RANKL is also expressed in collagen-induced arthritis (CIA) in which focal collections of osteoclasts are prominent at sites of bone destruction. To determine the role of RANK signaling events in the effector phase of CIA, we investigated effects of Fc-osteoprotegerin fusion protein (Fc-OPG) in CIA. After induction of CIA in Dark Agouti rats, test animals were treated with or without Fc-OPG (3 mg/kg/day) subcutaneously for 5 days, beginning at the onset of disease. Paraffin-embedded joints were then analyzed histologically and the adjacent bone assessed by histomorphometry. Osteoclasts were identified using TRAP staining and expression of the mRNA for OPG and RANKL was identified by in situ hybridization. The results indicated that short-term Fc-OPG effectively prevented joint destruction, even though it had no impact on the inflammatory aspects of CIA. In arthritic joints, Fc-OPG depleted osteoclast numbers by over 75% and diminished bone erosion scores by over 60%. Although cartilage loss was also reduced by Fc-OPG, the effects on cartilage were less striking than those on bone. In arthritic joints OPG mRNA was highly expressed and co-localized with RANK ligand, and treatment with Fc-OPG did not affect the expression of endogenous RANKL or OPG mRNA. These data demonstrate that short term Fc-OPG treatment has powerful anti-erosive effects, principally on bone, even though synovitis is not affected. These findings indicate the potential utility of disrupting RANK signaling to preserve skeletal integrity in inflammatory arthritis.
15142267 Induction of IL-10-producing CD4+CD25+ T cells in animal model of collagen-induced arthrit 2004 Induction of oral tolerance has long been considered a promising approach to the treatment of chronic autoimmune diseases, including rheumatoid arthritis (RA). Oral administration of type II collagen (CII) has been proven to improve signs and symptoms in RA patients without troublesome toxicity. To investigate the mechanism of immune suppression mediated by orally administered antigen, we examined changes in serum IgG subtypes and T-cell proliferative responses to CII, and generation of IL-10-producing CD4+CD25+ T-cell subsets in an animal model of collagen-induced arthritis (CIA). We found that joint inflammation in CIA mice peaked at 5 weeks after primary immunization with CII, which was significantly less in mice tolerized by repeated oral feeding of CII before CIA induction. Mice that had been fed with CII also exhibited increased serum IgG1 and decreased serum IgG2a as compared with nontolerized CIA animals. The T-cell proliferative response to CII was suppressed in lymph nodes of tolerized mice also. Production of IL-10 and of transforming growth factor-beta from mononuclear lymphocytes was increased in the tolerized animals, and CD4+ T cells isolated from tolerized mice did not respond with induction of IFN-gamma when stimulated in vitro with CII. We also observed greater induction of IL-10-producing CD4+CD25+ subsets among CII-stimulated splenic T cells from tolerized mice. These data suggest that when these IL-10-producing CD4+CD25+ T cells encounter CII antigen in affected joints they become activated to exert an anti-inflammatory effect.
15147345 The roles of interleukin-18 in collagen-induced arthritis in the BB rat. 2004 Jun Interleukin (IL)-18 is a member of the IL-1 cytokine family. Its expression is increased in rheumatoid arthritis synovium, and its proinflammatory effects have been demonstrated in experimental models of murine arthritis. Here, we investigate the actions of varying doses of recombinant rat IL-18 (rIL-18) on the course of type II collagen-induced arthritis (CIA) in BB rats, including clinical and immune events, plus splenic cytokine production. Small doses of rIL-18 (10 and 50 microg/rat) administered intraperitoneally (i.p.) increased arthritis incidence and severity (P < 0.01) when a low-potency CII preparation was used for immunization. IgG1 and IgG2a anti-CII antibody levels were significantly greater in rats given 10 and 50 microg rIL-18 doses than controls. rIL-18 significantly increased levels of proinflammatory cytokines [interferon (IFN)-gamma, IL-2, tumour necrosis factor (TNF)-alpha and IL-6] produced by splenocyte cultures. Larger doses of rIL-18 (300 microg/rat) suppressed arthritis and immunity. To ascertain whether the pro-arthritic effects of IL-18 could be attenuated, rats were treated with neutralizing rabbit anti-rIL-18 IgG before immunization with a high-potency CII preparation. When given serially for 3 weeks, the incidence and severity of CIA, in addition to anti-CII IgG2a and splenic IL-6 and IFN-gamma production, were all significantly reduced. Similar results were noted when antibody was given twice, just before arthritis onset. These results demonstrate that IL-18 plays an important proinflammatory role in the pathogenesis of CIA which is achieved, in part, by an immunostimulatory action. Neutralizing endogenous IL-18 with antibodies attenuated CIA, CII immunity and cytokine responses. These studies support the use of IL-18 antagonists as treatments for inflammatory arthritis.
14688369 Membrane-associated IL-1 contributes to chronic synovitis and cartilage destruction in hum 2004 Jan 1 IL-1 molecules are encoded by two distinct genes, IL-1alpha and IL-1beta. Both isoforms possess essentially identical activities and potencies, whereas IL-1alpha, in contrast to IL-1beta, is known to act as a membrane-associated IL-1 (MA-IL-1) and plays an important role in a variety of inflammatory situations. The transgenic (Tg) mouse line (Tg1706), which was generated in our laboratory, overexpresses human IL-1alpha (hIL-1alpha) and exhibits a severe arthritic phenotype characterized by autonomous synovial proliferation with subsequent cartilage destruction. Because the transgene encoded Lys(64) to Ala(271) of the hIL-1alpha amino acid sequence, Tg mice may overproduce MA-IL-1 as well as soluble IL-1alpha. The present study investigated whether MA-IL-1 contributes to synovial proliferation and cartilage destruction in the development of arthritis. Flow cytometric analysis revealed that both macrophage-like and fibroblast-like synoviocytes constitutively produce MA-IL-1. D10 cell proliferation assay revealed MA-IL-1 bioactivity of paraformaldehyde-fixed synoviocytes and the further induction of endogenous mouse MA-IL-1 via autocrine mechanisms. MA-IL-1 expressed on synoviocytes triggered synoviocyte self-proliferation through cell-to-cell (i.e., juxtacrine) interactions and also promoted proteoglycan release from the cartilage matrix in chondrocyte monolayer culture. Interestingly, the severity of arthritis was significantly correlated with MA-IL-1 activity rather than with soluble IL-1alpha activity or concentration of serum hIL-1alpha. Moreover, when the Tg1706 line was compared with the Tg101 line, which selectively overexpresses the 17-kDa mature hIL-1alpha, the severity of arthritis was significantly higher in the Tg1706 line than in the Tg101 line. These results suggest that MA-IL-1 contributes to synoviocyte self-proliferation and subsequent cartilage destruction in inflammatory joint disease such as rheumatoid arthritis.
14742260 Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tu 2004 Feb Local bone erosion and systemic bone loss are hallmarks of rheumatoid arthritis and cause progressive disability. Tumor necrosis factor (TNF) is a key mediator of arthritis and acts catabolically on bone by stimulating bone resorption and inhibiting bone formation. We hypothesized that the concerted action of anti-TNF, which reduces inflammation and parathyroid hormone (PTH), which stimulates bone formation, or osteoprotegerin (OPG), which blocks bone resorption and could lead to repair of local bone erosions and reversal of systemic bone loss. To test this, human TNF-transgenic mice with established erosive arthritis and systemic bone loss were treated with PTH, OPG, and anti-TNF, alone or in combination. Local bone erosions almost fully regressed, on combined treatment with anti-TNF and PTH and/or OPG, suggesting repair of inflammatory skeletal lesions. In contrast, OPG and anti-TNF alone led to arrest of bone erosions but did not achieve repair. Treatment with PTH alone had no influence on the progression of bone erosions. Local bone erosions all showed signs of new bone formation such as the presence of osteoblasts, osteoid formation, and mineralization. Furthermore, systemic bone loss was completely reversed on combined treatment and this effect was mediated by osteoblast stimulation and osteoclast blockade. In summary, we conclude that local joint destruction and systemic inflammatory bone loss because of TNF can regress and that repair requires a combined approach by reducing inflammation, blocking bone resorption, or stimulating bone formation.
15096482 Vaccination with an immunodominant peptide of bovine type II collagen induces an anti-TCR 2004 May T cell responses directed toward TCR-derived peptides have been shown to be an important regulatory mechanism of protection against autoimmunity. Here, we show that a naturally induced TCR-directed immune response can delay the onset of collagen-induced arthritis (CIA), an animal model of autoimmune rheumatoid arthritis in humans. DBA/1 mice were pretreated with an immunodominant peptide, p245-270, from bovine type II collagen (bCII) and were subsequently immunized with whole bCII for the induction of arthritis. The results showed that preactivation of p245-270-reactive cells delayed the onset and reduced the severity of CIA, compared with animals in the control group. Interestingly, the serum antibody response to bCII and the bCII-specific cytokine were not affected under these conditions. This result indicates that the observed protection was neither directly due to a lower antibody response nor due to the immune deviation of the anti-bCII T cell response. Furthermore, immunization with p245-270, but not bCII, induced a strong response to the B5 peptide, an immunodominant region of the TCR V(beta)8.2 (amino acids 76-101) that binds very strongly to I-A(q). These data suggest that at a critical phase in the loss of self-tolerance, an effective anti-TCR response, induced naturally, can regulate the pathogenic autoimmune response and thus may provide protection against autoimmunity.
12052456 Stage-dependent changes in trabecular bone turnover and osteogenic capacity of marrow cell 2002 Jun Rheumatoid arthritis (RA) is a disease characterized by inflammatory polyarthritis leading to destruction of the joints and reduction in bone mass. However, the relationship between bone mass and turnover is not yet clear in RA patients. To clarify the effect of bone turnover and marrow osteogenic capacity on mass and structure during the development of arthritis, we examined DBA1/J mice for 8 weeks after the first immunization with bovine type II collagen at the age of 9 weeks. Localized arthritis developed at 4 weeks and advanced arthritis at 6 weeks postimmunization. Urinary deoxypyridinoline levels in arthritic mice were significantly higher at 4 weeks, and levels were maintained thereafter. Their serum osteocalcin levels were significantly reduced compared with controls at 2 and 6 weeks, but did not differ significantly from those in the control group at 4 and 8 weeks. Three-dimensional (3D) trabecular bone volume of the proximal tibia measured by 3D microcomputed tomography (micro-CT) in the arthritic mice became significantly lower at 4 weeks and decreased further at 6 weeks compared with controls. Parameters of 3D trabecular bone structure, such as structure model index and trabecular bone pattern factor, were increased at 4 and 6 weeks, respectively. Trabecular osteoclast number increased and bone formation rates decreased at 8 weeks. The number of total bone marrow cells (BMCs), adherent stromal cells, and area of mineralized nodule formation in the tibia of arthritic mice were significantly reduced compared with controls at 6 weeks. Numbers of total fibroblastic colony-forming units (CFU-f) and alkaline phosphatase (ALP)-positive CFU-f colonies also decreased. However, the values of these osteogenic parameters corrected for the total BMCs and/or adherent stromal cells did not differ significantly between the arthritic and control groups. These data indicate that an increase in bone resorption led to the reduction in trabecular bone mass and deterioration of 3D structure during the localized arthritic stage. The reduction in bone marrow osteogenic potential in the advanced arthritic stage was due to the reduction in the number of total bone marrow cells, and differentiation of osteogenic cells was apparently unaffected. The reduction in bone formation may not be substantial in this arthritic model.
12109032 Minimal contribution of cell-bound antibodies to the immunoscintigraphy of inflamed joints 2002 Jun AIM: The cellular joint infiltrate in rheumatoid arthritis patients is rich in CD4-positive T-helper lymphocytes and macrophages, rendering anti-CD4 monoclonal antibodies (mAbs) suitable for specific immunoscintigraphy of human/experimental arthritis. Following intravenous injection, however, mAbs are present both in the free form and bound to CD4-positive, circulating monocytes and T-cells. Thus, the present study aimed at analyzing the relative contribution of the free and the cell-bound component to the imaging of inflamed joints in experimental adjuvant arthritis (AA). METHODS: AA rat peritoneal macrophages or lymph node l-cells were incubated in vitro with saturating amounts of 99mTc-anti-CD4 mAb (W3/25) and injected i.v. into rats with AA. RESULTS: In vitro release of 99mTc-anti-CD4 mAb from the cells was limited (on average 1.57%/h for macrophages and 0.84%/h for T-cells). Following i.v. injection, whole body/joint scans and tissue measurements showed only negligible accumulation of radioactivity in inflamed ankle joints (tissue: 0.22 and 0.34% of the injected activity, respectively), whereas the radioactivity was concentrated in liver (tissue: 79% and 71%, respectively), kidney, and urinary bladder. Unlike macrophages, however, anti-CD4 mAb-coated T-cells significantly accumulated in lymphoid organs, the inflamed synovial membrane of the ankle joints, as well as in elbow and knee joints. CONCLUSION: While the overall contribution of cell-bound mAbs to the imaging of arthritic joints with anti-CD4 mAbs is minimal, differential accumulation of macrophages and T-cells in lymphoid organs and the inflamed synovial membrane indicates preferential migration patterns of these 2 cell populations in arthritic rats. Although only validated for 99mTc-anti-CD4 mAbs, extrapolation of the results to other anticellular mAbs with similar affinity for their antigen may be possible.