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ID PMID Title PublicationDate abstract
9858426 How Canadian and US rheumatologists treat moderate or aggressive rheumatoid arthritis: a s 1998 Dec OBJECTIVE: To determine which second line agents Canadian and US rheumatologists use to treat patients with active rheumatoid arthritis (RA). METHODS: A one page survey was sent by fax or mail to all 263 members of the Canadian Rheumatology Association and 320 members of the American College of Rheumatology (10% random sample weighted by region) known to practice adult rheumatology. The survey asked for first and second treatment preferences in patients with (1) aggressive RA; (2) moderate RA; and (3) aggressive RA failing a trial of methotrexate (MTX) 25 mg. RESULTS: Altogether 231 (87.8%) Canadian and 230 (71.7%) US rheumatologists responded, and 214 responses in each survey were analyzable. In aggressive RA. MTX was the drug of first choice of most Canadian (68.7%) and US (78.5%) rheumatologists. Intramuscular gold was a drug of first choice for 14.5 and 1.9% of Canadians and Americans, respectively. 93.9% of Canadian and 90.2% of US respondents preferred single agents for the treatment of moderate RA. Among US rheumatologists. no clear leader emerged as a single agent alternative for the management of aggressive RA unresponsive to MTX. Most said they would use combination (38.3%) or triple (23.8%) therapy involving MTX plus sulfasalazine and/or hydroxychloroquine. 52.3% of Canadians preferred single agent therapy, with 34.6% choosing gold as an alternative to MTX. CONCLUSION: Canadian and US rheumatologists preferred MTX for the treatment of aggressive RA. Canadian rheumatologists saw a small but significant role for intramuscular gold. No single agent emerged as a clear alternative to MTX among US rheumatologists.
11281165 Involvement of interleukin-6 and prostaglandin E2 in periarticular osteoporosis of postmen 2001 In experimental arthritis, blocking of the receptor activator of nuclear factor kappaB ligand (RANKL) by osteoprotegerin (OPG) treatment prevents bone loss but not inflammation, suggesting that there are inflammation-related factors that regulate RANKL and OPG. However, it is not known which factors regulate RANKL and OPG in human inflammation-induced bone loss. To clarify the inflammation-related factors that play a role in periarticular osteoporosis in patients with rheumatoid arthritis (RA), the synovial fluid and synovium of the knee joint, and the periarticular cancellous bone of the femoral condyle were collected at surgery from postmenopausal women with RA or osteoarthritis (OA). All patients with RA had radiologic bone loss on the femoral condyles, while such a loss was not observed in patients with OA. The present study examined: (i) tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1beta and IL-6 levels in synovial fluid: (ii) TNFalpha, IL-1beta and IL-6 messenger RNA (mRNA) expression in the synovium and the cancellous bone that contained bone marrow; and (iii) IL-6 and prostaglandin E2 (PGE2) production in cultured osteoblast-lineage cells derived from collagenase-treated cancellous bone fragments. Inflammation of the knee joints in patients with RA was confirmed by significantly higher proinflammatory cytokine levels in the synovial fluid and the synovium than those seen in patients with OA. In patients with RA, mRNA expression of IL-6, but not TNFalpha and IL-1beta, in the cancellous bone and IL-6 and PGE2 production in the osteoblast-lineage cells were significantly higher than in patients with OA. These findings suggest, for the first time, that IL-6 is involved in periarticular osteoporosis in postmenopausal women with RA. IL-6 and PGE2 released from osteoblast-lineage cells could be, at least in part, responsible for human inflammation-induced bone loss.
9923652 New collagenolytic enzymes/cascade identified at the pannus-hard tissue junction in rheuma 1998 Dec Our aim was to investigate the collagenolytic potential and localization of matrix metalloproteinase-2 (MMP-2) in relation to its regulatory proteins membrane type MT1-MMP and tissue inhibitor of metalloproteinases-2 (TIMP-2) in rheumatoid arthritis (RA). For this purpose, we have used purification of MMP-2, MMP-8, MMP-9 and interstitial type I, II and III collagens; SDS-PAGE/densitometric collagenase activity assay; zymography; Western blotting; reverse transcriptase polymerase chain reaction; in situ hybridization; and immunofluorescence, ABC, ABC-APAAP double immunostainings. MMP-2 degraded human type II collagen almost as effectively as MMP-8, whereas MMP-9 did not cleave type II collagen. In synovial tissue, MT1-MMP, TIMP-2 and MMP-2 were found in synovial lining in fibroblast- and macrophage-like cells, in stromal cells and in vascular endothelium. MT1-MMP, TIMP-2 and MMP-2 were strongly expressed in the pannocytes of the invasive pannus at the interface, but staining was weak and/or there were few positive cells both "above" and "below" the soft-to-hard tissue (cartilage and/or bone) interface. Rheumatoid synovial tissue extract contained proteolytically active 62/59 kDa MMP-2 and 43 kDa MT1-MMP, but no free TIMP-2. These results indicate that components of the ternary MT1-MMP/TIMP-2/MMP-2 complex are coexpressed in the normal synovial lining and in its pathological extension on the hyaline articular cartilage. MMP-2 may participate in the remodeling of the normal lining and also seems to be localized/focalized to pannocytes at a site critical for tissue destruction in arthritis.
11339037 [Clinical variants and immunologic features of rheumatoid uveitis in children of different 2001 Jan Variability of clinical manifestations of rheumatoid uveitis, possibility of an atypical course (peripheral or panuveitis), and greater severity and specific features of the disease in case of its early (before the age of 3 years) manifestation are demonstrated on the basis of observations of 79 patients with rheumatoid uveitis. Despite systemic therapy with corticosteroids and cytostatics, no manifest post-steroid immunodeficiency was observed. Moderately expressed gammapathies were detected in 60% cases; hypoimmune states predominated, which were more often detected in children aged under 6 years. No cases of pronounced suppression of functional activity of lymphocytes were observed. Humoral and cellular response to persistent ophthalmotropic infections were observed more rarely than in children with uveitis of other etiology. Positive rheumatoid factor was detected in 9% cases, antinuclear antibodies in 60%. Antibodies to DNA were detected in the sera of 10% examinees, to native and denatured DNA in the lacrimal fluid of 21.2 and 16.7%, respectively. The causes of absence of obvious post-steroid immunodeficiency and relatively low rate of interorgan autosensitization in children with juvenile rheumatoid arthritis and uveitis are discussed. Further investigation of clinical and immunological correlations are needed for improving the prediction of the course of rheumatoid uveitis and development of treatment strategy.
9706428 Intra-observer reliability of commonly used outcome measures in rheumatoid arthritis. 1998 Jul OBJECTIVE: To determine the reliability of some commonly used outcome measures in patients with rheumatoid arthritis. METHODS: We studied 22 consecutive patients with rheumatoid arthritis enrolled in a clinical trial in a tertiary care center. The study design consisted of a test-retest, in which the same rheumatologist evaluated all of the patients twice, with an interval between evaluations of 90 to 120 minutes. Statistical analysis of the data consisted of calculation of the weighted Kappa (kw) and the intraclass correlation coefficient (ICC). RESULTS: For the Ritchie articular index, kappa w = 0.83, ICC = 0.49, p < 0.0001; tender joint count, kappa w = 0.82, ICC = 0.49, p < 0.0001; physician's global assessment, kappa w = 0.79, ICC = 0.48, p < 0.0001; disease activity score, kappa w = 0.79, ICC = 0.49, p < 0.0001; utilities, kappa w = 0.71, ICC = 0.48, p < 0.0001; swollen joint count, kappa w = 0.7, ICC = 0.47, p < 0.0001; patient's global assessment, kappa w = 0.58, ICC = 0.44, p < 0.0001; pain kappa w = 0.45, ICC = 0.41, p < 0.0001. CONCLUSIONS: The reliability of most of the outcome measures was good. It was higher for those measurements evaluated by a rheumatologist and for the composite indexes. Those requiring patient participation need to be improved.
9082928 Total lymphoid irradiation in rheumatoid arthritis. A ten-year followup. 1997 Mar OBJECTIVE: To report the findings of a 10-year followup of patients enrolled in a randomized trial of total lymphoid irradiation (TLI) versus chemotherapy for rheumatoid arthritis (RA). METHODS: A retrospective analysis of the charts of 19 patients who had been included in a randomized trial comparing TLI and chemotherapy for the treatment of RA. RESULTS: Ten years after the start of the trial, a higher number of TLI-treated patients had died (7 of 10), compared with patients who had received chemotherapy (2 of 9). In addition, 3 of the TLI-treated patients developed B cell-related malignancies, whereas no such malignancies developed in the control group. CONCLUSION: TLI was associated with a less-favorable long-term outcome than chemotherapy. These data stress the importance of careful long-term followup in experimental trials of immunosuppressive agents.
10853648 Synthesis of NF-kappaB activation inhibitors derived from epoxyquinomicin C. 2000 May 1 In order to develop new inhibitors of NF-kappaB activation, we designed and synthesized dehydroxymethyl derivatives of epoxyquinomicin C, namely, DHM2EQ and its regioisomer DHM3EQ. These derivatives were synthesized from 2,5-dimethoxyaniline in 5 steps. Since DHM2EQ was more active and less toxic than DHM3EQ, its stereochemical configuration was determined by X-ray crystallographic analysis. Each enantiomer of the protected DHM2EQ was separated by a chiral column and deprotected. DHM2EQ inhibited TNF-alpha-induced activation of NF-kappaB in human T cell leukemia cells, and also inhibited collagen-induced arthritis in a rheumatoid model in mice.
10989684 Severe pancytopenia after leflunomide in rheumatoid arthritis. 2000 Leflunomide is a novel drug recently introduced for treatment of rheumatoid arthritis as a DMARD (disease-modifying antirheumatic drug). So far, leflunomide has not been associated with severe bone marrow toxicity and pancytopenia. We report of a 62-year-old woman with a 14-year history of rheumatoid arthritis with bone marrow toxicity and reversible pancytopenia developing after treatment with leflunomide.
10083960 Psychosocial assessment of pain in patients having rheumatic diseases. 1999 Feb A variety of reliable and valid psychosocial assessment instruments have been developed. Many of these instruments are brief and easily incorporated into clinical practice settings. Measures of coping, self-efficacy, helplessness, and cognitive distortion are especially useful in understanding the pain experience in rheumatic disease populations. Information gleaned from psychosocial assessments is increasingly being used to guide pain treatment efforts. Recent research, suggests that treatment outcomes can be improved if one tailors psychosocial pain management protocols to address the particular problems identified by comprehensive psychosocial assessments. Considered overall, psychosocial assessment methods have much to offer the clinician working with patients having persistent pain. The current status of this field is promising, and as psychosocial assessment methods become even more fully integrated into clinical practice, they are likely to yield even greater insights into the pain experience of patients with rheumatic diseases.
9306499 [Matrix metalloproteinases]. 1997 Sep 1 Matrix-degrading enzymes, matrix metalloproteinases, are members of a unique family of Zinc-binding endopeptidases that are responsible for the metabolism of extracellular components in the tissue stroma. Their controlled expression is essential for normal processes such as wound healing and tissue remodeling, including embryogenesis. However, in many pathological conditions and events such as metastasis of malignant tumors and rheumatoid arthritis, the uncontrolled expression is evident.
10591973 [Present importance of direct immunologically based intervention strategies using anticyto 1999 Oct Rheumatoid arthritis (RA) is a chronic inflammatory multisystemic autoimmune disease of unknown origin. RA is clinically characterized by recurrent inflammation of joints, synovialitis, progressive destruction of cartilage or bone tissue and multiorgan involvement. Today all established therapies of RA are still unable to stop or even cure the disease. In most cases these therapies can only reduce progression. Furthermore, these therapies have substantial side effects, which can contribute to the increased mortality of disease. Therefore more effective therapies with fewer side effects are needed. In this context direct immunological intervention strategies increasingly gained interest to inhibit proinflammatory cytokines. In vivo and in vitro studies as well as experimental therapies documented the important role of the proinflammatory cytokines TNFalpha and IL-1 in RA. The therapy with TNFalpha-antibodies or receptor fusion proteins as well as IL-1 receptor antagonists proved to be clinically as well as immunologically highly effective as therapy of RA. The single dose treatment is associated with mild side effects only. In addition, trials using combined TNFalpha-antibody and methotrexate therapy gave promising results. However, potential severe side effects may occur after repeated therapy cycles or may be discovered after prolonged time of observation only (e.g., allergic reactions, induction of autoantibodies or malignancies). Therefore, at present these therapy options can only be recommended for selected patients, who are included into controlled clinical trials. In addition, repeated courses of therapy seem to lead to reduced therapeutical efficacy (especially in TNFalpha-antibody therapy). Further controlled studies with cytokine antagonists should especially address these problems and focus in particular on potential inductions of autoantibodies or malignancies as well as on additional long-term side effects. In contrast to direct inhibition of TNFalpha or IL-1 several further therapies indirectly influence these cytokines by interference with their synthesis or by alteration of the respective receptors. The importance of these therapeutical options has to be determined as well as the possibility of combination of established therapies with immunological intervention strategies.
11847790 Spirituality, resourcefulness, and arthritis impact on health perception of elders with rh 2000 Dec Arthritis is the leading chronic condition for older adults and the leading cause of disability in the United States. Providing holistic care to promote positive health perception and support healthy lifestyle decisions with these individuals is critical in attaining and maintaining quality of life. This study examined variables reflecting reactions to stress, lines of defense and resistance, and the basic core of humans in the context of the Neuman Systems Model in a convenience sample of 47 adults with a mean age of 70.4 years. The combined effects of the social, emotional, and physical impact of arthritis and additive or mediating effects of learned resourcefulness and spirituality on general health perception in older adults were investigated. Social, emotional, and physical impact together predicted health perception. The social impact of arthritis was a significant independent predictor for spirituality. Furthermore, spirituality and health perception were significantly correlated.
9599313 Salivary acidic proline-rich proteins in rheumatoid arthritis. 1998 Apr 15 In an ongoing attempt to investigate qualitative salivary parameters in diseases affecting salivary glands, patients with rheumatoid arthritis (RA) were examined. Patients were selected from the Oslo RA register for the present study if they fulfilled the following criteria: age 52-74 years, disease duration 10-20 years, and disability score as assessed by the Modified Health Assessment Questionnaire < or = 2.5. From these 105 patients, two subgroups of patients were selected, one group with pronounced sicca symptoms from eyes and mouth, and one group without such symptoms. Sicca symptoms were assessed using a postal questionnaire with the questions on dry mouth and dry eyes of the European classification criteria for Sjögren's syndrome. Patients were excluded from further examinations if they used medication that could cause dryness in eyes or mouth. Thus, nine patients remained in the sicca group (having four or more sicca symptoms), and ten matched RA patients were selected for the nonsicca group. A healthy sex- and age-matched control group (n = 10) was also examined. In a preliminary report we have shown that differences in flow rates between sicca and nonsicca RA patients were limited to lower values of unstimulated whole saliva. To further evaluate salivary changes in RA, a disease frequently associated with secondary Sjögren's syndrome, we have studied qualitative salivary parameters in these patients,' including secretory rates of proline-rich proteins (PRPs), statherins, and histatins. In the present report, phenotypes of PRPs, the ratio of PRPs derived from the two loci (PRH1 and PRH2), and PRP concentration and output in parotid and submandibular saliva derived from the two loci are presented. Parotid (PS) and submandibular saliva (SS) were collected from all individuals using 2% citric acid as a saliva stimulus. PRPs in PS and SS were identified using a SMART microchromatographic system with a Mono Q column and a Tris-HCl/NaCl gradient (method adapted from ref. 5). For PRPs, the primary polypeptide products are coded for on two loci (PRH1 and PRH2), which have three and two commonly occurring gene variants, respectively. On PRH1, the proteins PIF-s, Db-s, and Pa are coded for, whereas PRP-1 and PRP-2 are coded for on the PRH2 locus. As each protein variant has a postranscriptional cleavage product, individuals will exhibit four, six, or eight PRPs in their saliva, depending on whether they are homozygous at both, one, or neither of the two loci. Accordingly, 18 possible phenotypes may exist, but as few as three phenotypes were found in 79% of the 127 healthy individuals examined by Hay et al. The SMART system allows the determination of the different acidic PRPs present in saliva. Concentrations of the various phenotypes were calculated by peak integration versus pure PRP standards. Total PRP concentration derived from each locus was calculated as the sum of the concentrations of PRP variants from that locus.
9517763 Destruction and reconstruction of hand joints in rheumatoid arthritis. A 20 year followup 1998 Mar OBJECTIVE: To examine the radiographic endpoint changes and performed joint fusions and arthroplasties in hand joints in rheumatoid arthritis (RA) occurring over a 20 year period. METHODS: In 83 patients with recent (< 6 months) rheumatoid factor positive RA, radiographs were taken at 15 and 20 years from entry. The Larsen grades for 12 hand joints were evaluated, as well as the preoperative grades for reconstructed joints. Data of the performed hand joint fusions and arthroplasties were obtained. RESULTS: At 15 year followup the mean Larsen grade of wrist joints was 2.5, metacarpophalangeal (MCP) I-V 1.0-1.8, and interphalangeal I and proximal interphalangeal (PIP) II-V 0.7-0.9. At the endpoint the mean grades were: wrist joint 2.7, MCP I 1.1, MCP II 2.2, MCP III 1.9, MCP IV 1.3, MCP V 1.5, IP I and PIP II-V 0.7-1.0. Modified Larsen grade for carpometacarpal I was 1.6 and 2.0 at 15 year followup and endpoint, respectively. Reconstructive surgery was performed in 33/83 patients. The number of operations was 83, and 38 of them were wrist fusions. CONCLUSION: In this inception cohort, wrist joints had the highest destruction and the need for reconstructive surgery; the grade of destruction was lower in MCP and PIP joints, in this order. Possibilities of reconstructive surgery are discussed.
9682081 Triple arthrodesis in adults. 1998 May Surgical fusion of the subtalar, talonavicular, and calcaneocuboid joints historically evolved for the treatment of paralytic deformities of the foot where there was often notable bone deformity. Today most of these procedures are performed in adults for posttraumatic arthritis, rheumatoid arthritis, or end-stage posterior tibial tendon rupture with fixed bone deformity. Triple arthrodesis is a technically demanding procedure that generally involves a prolonged recovery time. When proper alignment is obtained, predictable and significant improvement in symptoms occurs, but the resultant loss of hindfoot motion is not without consequence. Residual discomfort and secondary arthrosis of the ankle and tarsometatarsal joints should be expected. Because of the complications of residual deformity, pseudarthrosis, avascular necrosis of the talus, and ankle and midtarsal arthritis, it has been recommended that it be used only as a salvage operation in older patients who have a painful, fixed deformity or disabling instability refractory to other treatment options. Despite these caveats, most patients who undergo triple arthrodesis for appropriate indications report significant improvement in their symptoms and level of function.
11824431 Severe liver damage with leflunomide. 2001 Oct Potentially life-threatening; close monitoring required.
10955323 Synovitis occurs in some clinically normal and asymptomatic joints in patients with early 2000 Aug OBJECTIVE: To determine if clinically asymptomatic knee joints in patients with recent onset arthritis reveal histological evidence of synovitis. METHODS: As part of a prospective study of patients with synovitis of less than one year duration, we performed blind needle biopsies on the knees of 20 patients who had synovitis elsewhere but no symptoms or detectable swelling or tenderness of the biopsied joint. RESULTS: Histologic evidence of synovitis was observed in 11 knees (55%). All patients with synovitis had evidence of synovial lining cell hyperplasia, increased vascularity, and lymphocytic infiltrates. Five of 6 patients with rheumatoid arthritis (RA) and 5 of 8 with undifferentiated arthritis had histological evidence of synovitis, but none of the 5 with reactive arthritis (ReA) had synovitis in the asymptomatic joints. Histologic evidence of synovitis persisted in some after clinical resolution of previous pain and swelling, while it occurred in others with no history of previous involvement of that knee. CONCLUSION: Even asymptomatic joints in patients with RA and undifferentiated arthritis of recent onset reveal histologic signs of synovitis. The earliest changes may occur before symptoms. Histologic changes also persist after resolution of previous early symptoms. Evidence of inflammation was not present in asymptomatic joints in our 5 patients diagnosed with ReA.
11710706 Relationships of matrix metalloproteinases and their inhibitors to cartilage proteoglycan 2001 Nov OBJECTIVE: To determine interrelationships in matrix turnover in articular cartilage and joint inflammation in rheumatoid arthritis (RA). METHODS: Synovial fluid was obtained from the knees of 63 RA patients; radiographs were evaluated to determine the RA stage. Concentrations of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), the 846 epitope, and the keratan sulfate (KS) epitope of aggrecan, the C-propeptide of cartilage type II procollagen (CPII; biosynthetic marker), the cleavage of type II collagen by collagenase (CIIC; generated neoepitope), and polymorphonuclear leukocyte elastase (PMNE; inflammation marker) were measured by immunoassay. Concentrations of the unsaturated disaccharides of hyaluronic acid (delta di-HA) and the proteoglycan glycosaminoglycan disaccharides of chondroitins 4 and 6 sulfate (delta di-C4S and delta di-C6S) were determined by high-performance liquid chromatography. RESULTS: MMP-3 was markedly increased in RA compared with osteoarthritis. Increases in TIMP-1 in RA were less pronounced and were inversely correlated with MMP-3 levels. CIIC was reduced in RA, as was the release of the KS epitope and delta di-C6S. In contrast, delta di-C4S and the 846 epitope were up-regulated. PMNE levels correlated with the 846 epitope and delta di-C4S, and more strongly with TIMPs 1 and 2. The changes may signify attempts at control of proteolysis in parallel with increased aggrecan turnover, which would favor matrix assembly. PMNE also correlated with MMP-9, and MMP-9 correlated with CPII. The delta di-HA level was decreased in RA and was inversely correlated with CPII and MMP-9 as well as with MMPs 2 and 3. In contrast, delta di-HA was directly correlated with TIMP-1 and the 846 epitope. These observations suggest that HA and PMNs may be involved in the control of proteolysis and cartilage proteoglycan assembly. CONCLUSION: Our observations provide new insights into the complex changes in cartilage turnover and PMN influx in RA joints.
10902750 Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or 2000 Jul OBJECTIVE: Leflunomide is a novel immunomodulating drug that has recently been approved as a disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). The aim of this study was to determine the relationship between the clinical effects of leflunomide and neutrophil migration. METHODS: The effects of leflunomide and methotrexate on neutrophil chemotaxis were studied in 15 RA patients who participated in a prospective, randomized, double-blind clinical trial. When possible, neutrophil numbers were counted in synovial fluid (SF) samples at baseline and after 14 days, 4 months, and 1 year of treatment. The chemotactic properties of peripheral blood neutrophils from RA patients treated with either leflunomide or methotrexate were studied by the Boyden chamber technique, using the activators formyl-methionyl-leucyl-phenylalanine (fMLP) and interleukin-8 (IL-8). The in vitro effects of A77 1726, the active metabolite of leflunomide, and methotrexate on peripheral blood neutrophils from 7 healthy control subjects were also investigated. RESULTS: Both therapy groups exhibited clinical improvement, including rapid reductions in SF neutrophil counts and reduced joint swelling and tenderness. On day 14, 3 of 7 patients who received leflunomide showed no detectable effusions. There was a significant effect on neutrophil chemotaxis (P < 0.001), which was similar for leflunomide and methotrexate. The direct effects on the neutrophils diminished over time. Incubation of peripheral blood neutrophils from healthy controls with A77 1726 confirmed the inhibitory effect on chemotaxis. CONCLUSION: Leflunomide treatment is beneficial in RA patients. Different mechanisms are operative in various phases of treatment, leading to decreased recruitment of inflammatory cells in the joints.
11550975 Dual inhibition of 5-lipoxygenase and cyclooxygenases 1 and 2 by ML3000 reduces joint dest 2001 Sep OBJECTIVE: To search for potential new therapies to inhibit the progression of joint destruction in patients with rheumatoid arthritis. METHODS: We evaluated the dual acting antiinflammatory drug ML3000 (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro- H-pyrrolizine-5-yl) acetic acid, a dual inhibitor of 5-lipoxygenase (5-LOX) as well as both cyclooxygenases (COX-1 and COX-2) in the rat model of adjuvant arthritis. On Day 0, female Lewis rats (5 per group) were injected intradermally with complete Freund's adjuvant at base of the tail. Treatment began on Day 2; the rats received ML3000 (20 or 80 mg/kg/day) twice daily 7 h apart for 28 days and were then sacrificed. To reduce pain, the positive control group and 2 treatment groups received paracetamol (3 mg/ml water). Joint histology was scored for synovial cell proliferation, fibroproliferative pannus, and cartilage and bone erosions, as well as diffuse leukocyte infiltrates. RESULTS: Daily doses of 20 or 80 mg/kg ML3000 significantly reduced the arthritis associated deficiency of body growth, the edema/erythema score, and splenomegaly. In the ankle joint, ML3000 significantly reduced the overall histological score, synovial cell proliferation, and bone/cartilage erosions, and inhibited the appearance of fibroproliferative pannus. The addition of paracetamol in the drinking water had no influence. No side effects were noted. CONCLUSION: ML3000 is an antiarthritic drug with a high gastrointestinal tolerability, which can reduce synovial cell proliferation and joint erosion and is capable of markedly suppressing prostaglandin synthesis.