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ID PMID Title PublicationDate abstract
15102876 Absence of a pharmacokinetic interaction between etanercept and warfarin. 2004 May Etanercept, a soluble recombinant human tumor necrosis factor receptor (TNFr) fusion protein, is effective and well tolerated in the treatment of rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). The primary objective of this study was to investigate the potential pharmacokinetic and pharmacodynamic interaction between a single dose of R- and S-enantiomers of warfarin and multiple doses of etanercept after administration of warfarin and etanercept alone and together. In a nonrandomized, three-period study, 12 healthy male subjects received a single oral 25-mg dose of warfarin after an overnight fast, followed by twice-weekly 25-mg subcutaneous doses of etanercept for seven doses. The last dose of etanercept was administered concurrently with a second dose of warfarin. Serial blood samples for plasma warfarin concentration measurement and international normalized ratio (INR) assessment were collected before and up to 144 hours after dose administration. Serial blood samples for serum etanercept concentration measurement were collected before and up to 60 hours after the sixth dose and 264 hours after the seventh dose. Etanercept did not affect the pharmacokinetics and pharmacodynamics of warfarin. All ratios of maximum serum concentration (C(max)) and area under the serum concentration versus time curve (AUC) for pharmacokinetics (R- and S-enantiomers of warfarin) and INR fell within the confidence interval of 0.8 to 1.25. Warfarin also did not cause a clinically significant alteration in the pharmacokinetics of etanercept. In conclusion, coadministration of etanercept and warfarin would not be expected to change the pharmacokinetics of either medication; therefore, no dosage adjustment is needed in cases in which warfarin and etanercept are coadministered.
11950023 Reduction of tumor necrosis factor induced nuclear factor-kappaB nuclear translocation and 2002 Apr OBJECTIVE: The antiinflammatory effects of glucocorticoids are mediated by several mechanisms, including inhibition of nuclear factor-kappaB (NF-kappaB) nuclear translocation and DNA binding. This mechanism is not evident in some cell types, including endothelial cells and rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). We determined the effect of glucocorticoids and tumor necrosis factor (TNF) on nuclear localization and DNA binding of the transcription factor NF-kappaB in osteoarthritic (OA) synovial tissue. METHODS: Explants of synovial tissue from patients undergoing joint replacement surgery for arthritis were placed in culture and treated with dexamethasone 10(-6) M for 18 h and again at 30 min prior to stimulation with TNF for a further 30 min. NF-kappaB and AP-1 DNA binding activities were determined by electrophoretic mobility shift analysis of nuclear extracts prepared from 6 whole tissue explants. Nuclear localization of NF-kappaB was determined by quantitative immunohistochemistry for Rel-A(p65) in thin sections of 5 synovial tissue explants. RESULTS: TNF induced NF-kappaB nuclear translocation and DNA binding in all OA synovial tissue explants, although there were no consistent effects on AP-1 DNA binding. Dexamethasone reduced TNF stimulated nuclear translocation of RelA(p65) in all 5 OA synovial explants analyzed by immunohistochemistry. Dexamethasone partially decreased NF-kappaB DNA binding in 5 of 6 TNF stimulated explants and 4 of 6 unstimulated explants. In cultured rheumatoid arthritis and OA fibroblast-like synoviocytes and Mono Mac 6 cells the effects of dexamethasone on NF-kappaB DNA binding were not evident. CONCLUSION: Dexamethasone partially inhibits TNF induced NF-kappaB DNA binding in human synovial tissue. It is feasible to use explants of intact fresh human synovium as a substrate for the action of antirheumatic drugs targeting a transcription factor.
11840457 Suppression of autoimmune arthritis in interleukin-1-deficient mice in which T cell activa 2002 Feb OBJECTIVE: To elucidate the roles of interleukin-1 (IL-1) in the development of 2 etiologically different rheumatoid arthritis (RA) models: the type II collagen (CII)-induced arthritis (CIA) model and the human T cell leukemia virus type I transgenic (HTLV-I Tg) mouse model. METHODS: For the CIA model, DBA/1J-background IL-1alpha-/-, IL-1beta-/-, IL-1alpha/beta-/-, and wild-type littermate mice were immunized with CII. For the HTLV-I Tg model, BALB/c IL-1beta-/- or IL-1alpha/beta-/- mice were crossed with HTLV-I Tg mice. The effects of IL-1 deficiency were assessed as follows: Development of arthritis was assessed both macroscopically and microscopically. Serum antibody titer was measured by enzyme-linked immunosorbent assay. Proliferative response of lymph node cells was assayed by measurement of (3)H-thymidine incorporation. Expression of T cell surface molecule CD40 ligand (CD40L) and OX40 was determined by multicolor flow cytometric analysis. RESULTS: The development of arthritis was markedly suppressed in IL-1alpha/beta-/- mice in both models, although the effect was less prominent in HTLV-I Tg mice. Deficiency of only IL-1alpha or only IL-1beta was also associated with disease suppression. Antibody production after immunization with CII was normal in IL-1alpha/beta-/- mice, while autoantibody production was suppressed in IL-1alpha/beta-/- HTLV-I Tg mice. In IL-1alpha/beta-/- mice, the T cell proliferative response against CII was greatly reduced in both the CIA and the HTLV-I Tg models, suggesting inefficiency of T cell activation. Furthermore, expression of CD40L and OX40 on T cells was greatly reduced in IL-1alpha/beta-/- mice. CONCLUSION: These observations suggest that T cell activation by IL-1 is important for the development of autoimmunity and arthritis in these mice.
14647814 [Uveitis in juvenile idiopathic arthritis]. 2002 Jan OBJECTIVE: To evaluate the frequency of chronic anterior uveitis in patients with juvenile idiopathic arthritis and its association with the presence of antinuclear antibodies. PATIENTS AND METHODS: We retrospectively studied 72 patients with juvenile idiopathic arthritis. All of them were submitted to slit-lamp examination of the anterior chamber at diagnosis. Both antinuclear antibodies and rheumatoid factor were determined. Patients with positive results for antinuclear antibodies were evaluated every three months and those with negative results were assessed every six months. RESULTS: Forty patients were male (55.5%) and 36 were Caucasoid (50%). The mean age at the onset of juvenile idiopathic arthritis was 6.4 years (range = 1 to 14 years) and the mean age at the beginning of the study was 10.4 years (1 to 19 years). According to the type of disease at onset, 32 were pauciarticular (44.4%) (17 boys and 15 girls), 30 were polyarticular (41.6%) (17 boys and 13 girls) and 10 were systemic (14%) (6 boys and 4 girls). We observed chronic anterior uveitis in five patients (6.5%) (mean age = 11.4 years). Among them, four (80%) had pauciarticular juvenile idiopathic arthritis at disease onset (three girls with type I juvenile idiopathic arthritis and positive antinuclear antibodies and one boy with type I juvenile idiopathic arthritis and negative antinuclear antibodies) and one girl with polyarticular juvenile idiopathic arthritis (negative antinuclear antibodies and rheumatoid factor). In this group, the mean age at the onset of juvenile idiopathic arthritis was 5.1 years and the mean age of uveitis onset was 9 years. Antinuclear antibodies were positive in 3/5 patients (60%) with uveitis. Antinuclear antibodies were positive in 12% of the patients without uveitis (n = 67). Among the patients with uveitis, three had only one flare and the other two had four flares with cataract. The frequency of antinuclear antibodies was statistically higher in the patients with uveitis (P< 0.05). CONCLUSION: Although the incidence of uveitis in our study was lower than that reported in the literature, the frequency of uveitis was higher in females, in those with pauciarticular juvenile idiopathic arthritis and in patients with positive antinuclear antibodies.
15195117 Possible involvement of MIP-1alpha in the recruitment of osteoclast progenitors to the dis 2004 Sep In the rat model of rheumatoid arthritis, a marked formation of osteoclasts is found in the distal tibia and the metatarsal bone. It was therefore postulated that osteoclast progenitors would be increased in the bone marrow cavities of rats with adjuvant-induced arthritis (AA rats). Bone marrow cells obtained from tibia of AA rats were cultured to form cells in the osteoclast lineage to access the number of osteoclast progenitors. Unexpectedly, only a suppressed level of osteoclast progenitors was detected in the diaphyseal bone marrow of tibia in AA rats. Distribution of osteoclast progenitors in the bone marrow cavity was examined, and it was shown that osteoclast progenitors accumulated in the distal tibia. Macrophage inflammatory protein (MIP)-1alpha, an osteoclastogenic CC chemokine, was expressed in ED-1-positive macrophages localizing in the distal tibia with marked bone destruction. Chemotaxis studies showed that MIP-1alpha expressed significant activity towards bone marrow cells. The suppressed level of osteoclastogenesis in bone marrow cells of AA rats was restored to a normal level by the addition of MIP-1alpha. It was suggested that MIP-1alpha is involved in the migration of osteoclast progenitors to the distal tibia as well as in osteoclastogenesis in AA rats. In these rats, in situ hybridization of the distal tibia with a high level of bone destruction showed significant expression of Receptor activator nuclear factor kappaB ligand (RANKL) messenger RNA in aggregates of multinucleated osteoclast-like cells present in the bone marrow cavity, a unique pathological feature for these rats. Migrated osteoclast progenitors are thought to be efficiently differentiated into osteoclasts in response to RANKL expressed by the aggregates of osteoclast-like cells under the influence of the MIP-1alpha. Such positive-feedback regulation of osteoclastogenesis could result in the highest recruitment of active osteoclasts in the area of marked bone destruction.
12209529 Modulation of multiple experimental arthritis models by collagen-induced arthritis quantit 2002 Aug OBJECTIVE: Collagen-induced arthritis (CIA) is a model of inflammatory arthritis with many similarities to rheumatoid arthritis (RA). We previously mapped in F(2) offspring of CIA-susceptible DA and CIA-resistant F344 rats, 5 quantitative trait loci (QTLs) for which F344 alleles were associated with reduced CIA severity. In the present study, we sought to characterize the independent arthritis-modulating effects of these 5 QTLs. METHODS: CIA-regulatory regions were transferred from the F344 genome to the DA background or vice versa by repeated backcrossing. The arthritis-modulating effects of the transferred alleles were determined by comparing the severity of experimentally induced arthritis in congenic rats with that in DA rats. RESULTS: Congenic lines with either the F344 major histocompatibility complex (MHC) on the DA background or the DA MHC on the F344 background were resistant to CIA, confirming both MHC and non-MHC contributions to the genetic regulation of CIA. F344 alleles at the Cia3 and Cia5 regions of chromosomes 4 and 10 reduced CIA severity relative to that observed in DA rats. F344 Cia4 and Cia6 regions of chromosomes 7 and 8 failed to significantly alter CIA severity. Arthritis-modifying effects of Cia4 and Cia6 were, however, detected in pristane-induced and/or Freund's incomplete adjuvant oil-induced arthritis. The arthritis-modifying effects of the non-MHC CIA-regulatory loci differed in males and females. CONCLUSION: These congenic lines confirmed the existence and location of genes that regulate the severity of experimental arthritis in rats. Mechanisms responsible for the sex-specificity of individual arthritis-regulatory loci may explain some of the sex differences observed in RA and other autoimmune diseases in humans.
15311562 Lumiracoxib (Prexige): a new selective COX-2 inhibitor. 2004 Jun Lumiracoxib, a new selective COX-2 inhibitor, has been recently approved in England and Mexico for the treatment of acute and chronic pain. Although it is the fifth COX-2 inhibitor to come to the market, it has a unique structure that could prove to be important in the adverse event profile. Double blind randomised trials have proved its efficacy in acute pain, dysmenorrhea, rheumatoid arthritis and osteoarthritis. Its gastrointestinal safety profile has been studied in multiple trials. The main clinical trail, therapeutic arthritis research and gastrointestinal event trial, has as primary end point: perforations, obstructions and bleeding and as secondary end points: cardiovascular, renal and hepatic safety profile. The results of this trial will probably change the way we look at selective COX-2 inhibitors.
12476631 [Anti-TNF-alpha treatment and spondyloarthropathies]. 2002 Nov Spondyloarthropathies are characterized by both axial and peripheral joint involvement, by the association with "other diseases" mainly Psoriasis, Crohn's and Anterior Uveitis and by the high prevalence of HLA B-27. While disease modifying drugs, such as Methotrexate or Sulfasalazine, are only partially effective in controlling peripheral arthritis, the treatment of the axial part remained only symptomatic. The recently introduced anti-TNF-alpha drugs Infliximab (Remicade) and Etanercept (Enbrel) for the treatment of Crohn's disease and Rheumatoid Arthritis has been expended to Spondyloarthropathies with highly promising results. The rationale and the early beneficial results of this new approach in spondyloarthropathies are reviewed.
15299208 Development and clinical application in arthritis of a new immunoassay for serum type IIA 2004 Type II collagen, the most abundant protein of cartilage matrix, is synthesized as a procollagen molecule including the N-(PIINP) and C-(PIICP) propeptides at each end. Type II procollagen is produced in two forms as the result of alternative RNA splicing. One form (IIA) includes and the other form (IIB) excludes a 69-amino acid cysteine-rich globular domain encoded by exon 2 in PIINP. During the process of synthesis, these N-propeptides are removed by specific proteases and released in the circulation, and their levels are believed to reflect type II collagen synthesis. In this chapter we describe the development of a specific enzyme-linked immunosorbent assay (ELISA) for the measurement of the IIA form of PIINP (PIIANP) in serum based on a polyclonal antibody raised against recombinant human exon 2 fusion protein of type II procollagen. We show that this ELISA is highly specific for circulating PIIANP and has adequate technical precision. In patients with knee osteoarthritis and rheumatoid arthritis, serum PIIANP was decreased by 53% (p < 0.0001) and 35% (p < 0.001), respectively, suggesting that type IIA collagen synthesis is altered in these arthritic diseases. The measurement of serum PIIANP may be useful for the clinical investigation of patients with joint diseases.
12718738 Overview of the use of the anti-TNF agent infliximab in chronic inflammatory diseases. 2003 Feb Anti-inflammatory therapy with monoclonal antibodies (mAbs) directed against tumour necrosis factor (TNF)-alpha has emerged as a major advancement in the treatment of various immune mediated diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn's disease. TNF-alpha seems to play a major pathogenic role in these chronic immune-mediated inflammatory diseases. Infliximab (Remicade), Centocor, Inc., Malvern, PA, USA), a chimaeric mAb, binds to soluble and membrane bound TNF-alpha, but not to TNF-beta. Infliximab is able to effectively regulate and mediate inflammatory processes involved in a number of different disease states. Many clinical trials in these diseases have demonstrated that biological therapy with mAbs directed against TNF-alpha is effective and relatively safe.
12089617 [The "Hospital Real de San Josef de los Naturales" and the rheumatic conditions found in N 2002 The rheumatic conditions found in New Spain during the sixteenth century were not different from those seen in Mexico in present times. We present the humoral conceptions on which medical theory was based in those times, and the contributions made by Alonso López de Hinojosos during his practice in the Hospital Real de San Josef de los Naturales, in Mexico City. Among them were the clinical distinction between gout and rheumatoid arthritis more than one hundred years before Sydenham, and the identification of arthritis and ocular involvement associated with a contagious disease more than three hundred years before Reiter. We conclude that the analysis of ancient medical traditions is an interesting and fruitful enterprise.
11951162 [Physical activity after shoulder arthroplasty]. 2002 Mar A hemi- or total shoulder arthroplasty was performed in 171 patients between 1992 and 1997. We examined 118 patients under the age of 70 regarding their level of physical activity. For a pre- and postoperative comparison we divided the patients in two groups. Group one included all patients with osteoarthritis, rheumatoid arthritis, instability associated arthritis, avascular necrosis and other arthropathies. Group two included acute fractures and fracture sequelae. The postoperative outcome was functionally assessed by using the Constant score. There was an average Constant score of 60,9 for group one and 67,1 for group two. Both groups showed a domination of activities with motion patterns unspecific for the shoulder. There were more patients in group two reporting activities which depend on a good or very good shoulder function. There is no general estimation for the ability to be active in sports after shoulder arthroplasty. An individual assessment of the shoulder function is essential. Important criterias beside motivation and age are the status of the rotator cuff and the soft tissue balancing. The correct indication for shoulder arthroplasty as well as the preoperative planning and the postoperative rehabilitation program are essential for a good functional outcome and the key for physical activity after shoulder arthroplasty.
11833675 Comparison of three dsDNA-ELISAs with regard to their efficiency in the diagnosis of syste 2002 We compared the performance of three commercially available anti-double-stranded DNA antibody ELISA kits with respect to their precision, accuracy, linearity, and the detection limit. We tested six sets of patients (lupus erythematosus, scleroderma, rheumatoid arthritis, psoriatic arthritis, hepatitis C, malignancies) to assess specificity, sensitivity, and diagnostic efficiency of the three assays. The diagnostic efficiency of the Crithidia luciliae immunofluorescence test was analyzed as a reference. The sensitivity of the evaluated enzyme immunoassays ranged from 55.6 to 66.7%, the specificity from 98.4 to 100%, and the diagnostic efficiency from 90.2-92.7%. All ELISAs were superior to the immunofluorescence test, both with respect to sensitivity, specificity, and diagnostic efficiency. The commercial kits tested were comparable with respect to their performance characteristics.
12445524 Anticytokine therapy--new approach to the treatment of autoimmune and cytokine-disturbance 2002 Dec We pioneered the theory (Nature, 1974) that hyperproduced interferons (cytokines) can bring autoimmune diseases (AD) and neutralizing these cytokines can be therapeutic. In 1975 we first performed successful anticytokine therapy using anti-IFN-alpha antibodies in patients with rheumatoid arthritis (RA). In 1989 we proposed also treating AD including AIDS by removing TNF-alpha and IFN-alpha. Our theory has been widely confirmed: injections of IFN-alpha and -gamma can exacerbate AD, while antibodies to IFN-alpha and -gamma and TNF-alpha can be therapeutic. Anti-IFN-gamma may be a universal treatment for Th1 AD. We had good results using anti-IFN-gamma to treat RA, multiple sclerosis (MS), transplant rejection, alopecia areata, vitiligo, psoriatic arthritis, psoriasis and others. For Th1/Th2 diseases, antagonists to cortisol could prevent the Th1-Th2 shift and allow treatment as a Th1 disease. Anticytokine therapy can also be therapeutic in many neuropsychiatric diseases. Every disturbance of homeostasis may lead to cytokine disturbance. IL-10 may restore homeostasis by inhibiting the production of certain Th1 cytokines and could be used to treat some embryonic disturbances and AD including MS.
12112647 Syngeneic fibroblasts transfected with a plasmid encoding interleukin-4 as non-viral vecto 2002 May BACKGROUND: No effective long-term treatment is available for rheumatoid arthritis. Recent advances in gene therapy and cell therapy have demonstrated efficiency in collagen-induced arthritis (CIA). Interleukin-4 (IL-4) is already known to be efficient in CIA in systemic injection or administered by gene therapy. This study was designed to evaluate the effect of a non-viral gene therapy of CIA, involving injection of syngeneic fibroblasts transfected with a plasmid encoding for IL-4. METHODS: Immortalised fibroblasts from DBA/1 mice (DBA/1/0 cells) were transfected with a plasmid expressing IL-4 cDNA (DBA/1/IL-4 cells). Xenogeneic fibroblasts from Chinese hamster ovary (CHO) transfected with a plasmid expressing IL-4 cDNA (CHO/IL-4) were studied also. The cells were engrafted in mice developing CIA by subcutaneous injection of 3 x 10(6) DBA/1/0 or DBA/1/IL-4 or CHO/IL-4 cells. RESULTS: Injection of DBA/1/IL-4 cells, on days 10 and 25 after immunisation, was associated with a significant and lasting improvement in the clinical and histological evidence of joint inflammation and destruction as compared with DBA/1/0 and CHO/IL-4 cells. DBA/1/IL-4 cell treatment decreased also the production of IgG2a antibody to CII and the proliferation of CIIB-specific nodal T cells. Later treatments (engraftments on days 23 and 35 after immunisation) exerted also an anti-inflammatory effect, as evaluated on clinical and histological signs of CIA. CONCLUSIONS: Taken together, these findings indicate that systemic administration of syngeneic cells transfected with an anti-inflammatory cytokine gene, namely IL-4, with a non-viral method is effective in CIA and may attenuate the cytokine imbalance seen in this disease.
15287356 [Epidemiology and prognostic aspects of ankylosing spondylitis]. 2004 Mar The spondyloarthritides (SpA) comprise ankylosing spondylitis (AS), psoriatic SpA (PsSpA), reactive SpA (ReSpA), arthritis associated with chronic inflammatory bowel disease (SpAIBD) and undifferentiated SpA (uSpA). There are characteristic clinical features of SpA: inflammatory back pain (IBP), asymmetric peripheral arthritis, enthesitis, anterior uveitis, positive family history and others. The SpA, mainly AS, are strongly associated with HLA B27. AS is the most frequent and potentially most severe subtype, next to PsSpA. The prevalence of all SpA is rather high and not much different from rheumatoid arthritis (RA) and AS patients carry a burden of disease similar to RA patients. The prognosis of AS has not been extensively studied but some factors have been identified. There is a clear role for imaging modalities in the diagnosis of AS. Changes in the sacroiliac joint as detected by radiography still constitute the basis for the diagnosis of AS (New York criteria 1984). A diagnosis of sacroiliitis as made by magnetic resonance imaging (MRI) provides more objective evidence to a diagnosis of IBP arguing in favour of SpA which is defined on the basis of the ESSG criteria 1991 mainly on a clinical basis. Radiographic spinal changes such as syndesmophytes are important for the staging and outcome of AS. MR based assessment of spinal changes in are now being increasingly used to assess disease activity of AS patients. The presence of spinal radiographic changes at time of presentation was found to be the best predictor of further deterioration using the score modified SASSS' in a recent study. Other clinical features such as hip arthritis, early onset of disease, dactylitis, oligoarthritis, limitation of spinal mobility and poor efficacy of nonsteroidal antiinflammatory drugs were found to also have negative prognostic value.
15248231 Absence of antibodies to cyclic citrullinated peptide in sera of patients with hepatitis C 2004 Jul OBJECTIVE: To determine if antibodies to cyclic citrullinated peptide (anti-CCP) are found in chronic hepatitis C virus (HCV) infection. METHODS: Rheumatoid factor (RF) and anti-CCP were measured in sera from 50 patients with HCV infection but without cryoglobulinemia, sera from 29 patients with mixed cryoglobulinemia (including 13 with rheumatic symptoms and 5 with arthritis), and sera from 20 normal blood donors. Anti-CCP was measured by second-generation enzyme-linked immunosorbent assay (ELISA). RESULTS: No sera with elevated anti-CCP were found in patients with HCV infection without cryoglobulinemia, and in that population, the maximum anti-CCP was 10 units, well below the positive cutoff of 20 units. Positive findings on RF testing >13 IU/ml were present in 22 (44%) of the HCV patients, with RF >50 IU/ml in 8 (16%) and a maximum RF of 526 IU/ml. Of the cryoglobulinemia patients, 22 (76%) had positive results on tests for RF, including 18 (62%) with RF >50 IU/ml and a maximum RF of 5,540 IU/ml. Two (6.9%) of the cryoglobulinemia patients had borderline-positive findings on tests for anti-CCP (25 units and 37 units), which were false-positive results caused by nonspecific binding in the ELISA. No association between the RF and the anti-CCP concentrations was found. CONCLUSION: Whereas RF was frequent in patients with HCV infection with and without cryoglobulinemia, anti-CCP was not observed in patients with uncomplicated HCV infection. Borderline-positive anti-CCP results were observed infrequently in patients with mixed cryoglobulinemia and were caused by nonspecific binding to plastic. Measurement of anti-CCP may help in diagnosing RA in patients with chronic HCV infection.
15338486 Effect of methotrexate therapy on bone mineral density and body composition in rat adjuvan 2004 Sep OBJECTIVE: To test whether methotrexate (MTX) therapy of rat adjuvant arthritis (AA) prevents loss of bone mineral density (BMD) and loss of adipose and lean body mass compared to pair-fed controls with untreated rat AA (positive controls) and rats without AA (negative controls). METHODS: AA was induced by a Mycobacterium butyricum injection at the base of the tail of 5-week-old female Lewis rats. The MTX-treated group was injected with adjuvant and then treated twice weekly with MTX (1.0 mg/kg/wk intraperitoneally). To control for the effects of AA on appetite and weight, food given to control animals and MTX-treated rats with AA was limited to that consumed by rats with untreated AA. At 42 days post-adjuvant injection, the animals were sacrificed and tibial BMD was measured. Body composition was analyzed for percentage fat, protein, ash, and water. RESULTS: There was no difference in ankle edema score or ankle width between the negative controls and MTX-treated group at necropsy. BMD was significantly higher in the negative controls versus positive controls and MTX-treated and in MTX-treated versus positive controls. There was significantly less body fat and protein and greater body water in the positive controls and MTX group compared to the negative controls. CONCLUSION: MTX prevents loss of BMD in the tibia in the rat AA model compared to positive controls. While MTX is effective in lowering inflammation in rat AA, there are still significant losses in BMD and body composition, which may have implications for rheumatoid arthritis.
15187239 Biological therapies in the spondyloarthritides--the current state. 2004 Sep Therapeutic options for patients suffering from the more severe spondyloarthritides (SpA) have been rather limited in the last decades. Evidence is now accumulating that anti-tumour necrosis factor (TNF) therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published concerning more than 1000 patients with AS and PsA, this treatment seems to be even more effective than in rheumatoid arthritis (RA). The anti-TNFalpha agents currently available, infliximab (Remicade), etanercept (Enbrel) and adalimumab (Humira), are approved for the treatment of RA in the USA and Europe. The situation for SpA is different from RA because there is an unmet medical need, especially in AS, since no therapies with disease-modifying anti-rheumatic drugs (DMARDs) are available for severely affected patients, especially those with spinal disease. Thus, TNF blockers may even be considered a first-line treatment in a patient with active AS and PsA whose condition is not sufficiently controlled with non-steroidal anti-inflammatory drugs (NSAIDs) in the case of axial disease, and sulphasalazine or methotrexate in the case of peripheral arthritis. For infliximab, a dose of 5 mg/kg is required, and intervals of between 6 and 12 weeks are necessary to constantly suppress disease activity-also a major aim for long-term treatment. The standard dosage of etanercept is 2 x 25 mg subcutaneously per week. There are almost no studies yet on adalimumab (standard dose in RA, 20-40 mg subcutaneously every 1-2 weeks) in SpA. Infliximab and etanercept are now both approved for AS in Europe. The efficacy of etanercept was first demonstrated in PsA, and it is now approved for this indication in the USA and Europe. There is preliminary evidence that both agents also work in other SpA, such as undifferentiated SpA (uSpA). Studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis may be preventable, but it remains to be shown whether patients benefit from long-term anti-TNF therapy and whether radiological progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. These can largely be prevented by appropriate screening. As it stands now, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.
15105968 Amelioration of murine antigen-induced arthritis by dehydroepiandrosterone (DHEA). 2004 May OBJECTIVE AND DESIGN: Sex hormones have immunomodulatory properties and may play an important role in the pathogenesis of autoimmune diseases like rheumatoid arthritis (RA). This study sought to examine the effects of the natural weak androgen dehydroepiandrosterone (DHEA) and its metabolite androstenediol (AED) on the development of murine antigen-induced arthritis (AIA). METHODS: DHEA and AED were administered orally, approximately 10 mg/day, from the time of AIA induction (i.e., 3 weeks after start of immunization) in young male as well as young and old female C57BL/6 mice. The effects were assessed in terms of joint swelling, histological changes, and cell-mediated and humoral immunity. RESULTS: Compared to untreated AIA animals, continuous administration of DHEA decreased knee joint swelling during acute and chronic AIA, as well as histological signs of inflammation and joint destruction during chronic AIA. These effects were age- and gender-independent. Delayed-type hypersensitivity (DTH) to the specific antigen methylated bovine serum albumin (mBSA) was significantly reduced, but there were no changes in the balance of the T helper (Th) cell subsets Th1/Th2, as tested by the ratio of IgG isotypes in the sera. Whereas serum levels of IgG antibodies to mBSA were not influenced, the formation of IgG autoantibodies to the matrix constituents collagen type I, collagen type II, and cartilage proteoglycans was significantly inhibited. In all experiments, the effects of AED were not significantly stronger than those of DHEA. CONCLUSIONS: Administration of exogenous DHEA ameliorates the severity of acute and chronic AIA, presumably by suppressing cell-mediated immunity against mBSA (the inducing antigen) and formation of autoantibodies. However, because of the fundamentally different DHEA physiology in rodents, the role of such a replacement therapy in human RA deserves further elucidation.