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ID PMID Title PublicationDate abstract
10805043 Drugs-nutrient interactions: a potential problem during adolescence. 2000 Mar The concept of drug-nutrient interactions is not new, but it has only recently gained currency in medicine. Although the elderly are normally considered to be at particular risk, other groups may also be at risk: infants, adolescents, pregnant women, alcohol and tobacco users, etc. In infants and adolescents there are several factors that may influence the possible interactions: firstly, nutrient needs are usually higher, mainly micronutrients; systems for detoxification of anutrients are not complete; the tendency to restricted diets (especially girls) that are unable to cover the actual recommended intakes for a number of micronutrients (i.e. vitamins); and the dangerous increase in alcohol consumption either in males or females. Administration of drugs in population with adequate vitamin intake is usually not a problem, but administration of drugs in those with borderline intake of vitamins or in patients with low nutritional status can result in symptomatic vitamin deficiency states. The groups at risk of poor vitamin status are smokers (a high proportion of adolescents are active smokers); dieters (skipping meals and dieting to lose weight frequently compromise micronutrient intake, and it should be considered that it is extremely difficult to meet all the requirements at intakes of less than 1,200 calories per day), oral contraceptive users, and pregnant and lactating women, excessive alcohol users, etc. The chapter also focuses on the case of folate: rapidly dividing tissues during the adolescent growth spurt increase requirements for folate. Because of this increased need, folate status appears to be of concern during the age of this rapid growth. A variety of drugs are known to interfere with vitamin utilization by blocking or altering transformation of the vitamin to its metabolically active form. Serum folate levels are known to be low in a high percentage of patients with rheumatoid arthritis, suggesting that aspirin alters the transport of folate by competition for binding sites on serum proteins. Methotrexate, a drug commonly used at low doses for the treatment of psoriasis, rheumatoid arthritis and certain liver disorders, limits the availability of methyl groups derived from one-carbon metabolism by inhibiting competitively a key enzyme in the intracellular folate metabolism. In humans, the antiepileptic drug valproic acid (VPA) is associated with two major adverse effects: teratogenicity and folate deficiency. The mechanisms by which VPA exerts the teratogenic or antifolate effect remain unclear, but an alteration in the methionine cycle is the strongest hypothesis proposed.
9458211 Clinical outcome of 149 patients with polymyalgia rheumatica and giant cell arteritis. 1998 Jan OBJECTIVE: To assess the clinical outcome of patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). METHODS: All charts of consecutive patients with a diagnosis of PMR and/or GCA attending a tertiary referral center from June 1989 to February 1996 were reviewed following a predetermined protocol. Subsequently, the majority of patients (90%) were assessed clinically or by telephone interview. Registered variables included demographic data, disease characteristics, prednisone dosage and duration, comorbidities, and clinical outcomes. RESULTS: There were 149 patients (133 with PMR alone, 7 with GCA alone, 9 with both); 94 (63%) were females; the mean age was 68 +/- 9 years, and the mean disease duration from the first symptom to the rheumatology consultation was 13 +/- 12 weeks (1-99). Typical clinical features of PMR were present in patients with PMR. Synovitis was observed in 26 patients. The presenting symptoms for GCA were typical features in 13 patients and blindness in 3 (2%) patients. Mean followup was 3.7 +/- 2 years. Comorbid conditions were present in 71 patients: 12 patients had hypertension, 13 had fractures, 8 diabetes, 29 cataract, 8 major infection, and 37 had other complications. Cancer was diagnosed in 4 patients and 6 patients had died. Prednisone was prescribed in 148 patients (mean dose 23 +/- 14 mg) for a mean time of 28 +/- 29 mo. Nonsteroidal antiinflammatory drugs were prescribed in 51 (34%) patients and methotrexate in 2. Disease remission was achieved in 81 (54%) patients (72 remissions, 9 presumed remissions) in whom steroid therapy had been stopped. Another 54 (36%) patients were still taking prednisone at the time of the interview, all were in clinical remission. Seventeen patients developed rheumatoid arthritis subsequent to the diagnosis of PMR. CONCLUSION: PMR and GCA should not necessarily be considered diseases with favorable outcome. In many of our patients, steroids were required for a prolonged period. Some patients developed significant complications attributable to steroid therapy. A significant number of patients progressed to rheumatoid arthritis.
11687037 Methotrexate for treating juvenile idiopathic arthritis. 2001 BACKGROUND: In both adult rheumatoid arthritis (RA) and juvenile arthritis, the focus has shifted from 'inflammation parameters' to more patient centered disability outcomes. In RA this resulted in the development of the Outcome Measures in Arthritis Clinical Trials (OMERACT), and in juvenile arthritis the Pediatric Rheumatology International Trials Organization (PRINTO) core set. This PRINTO-core set was established using a combination of statistical and consensus formation techniques. This core set contains a number of patient centered disability measures. This review systematically searched the available literature and reports the available evidence of efficacy of MTX, with special focus on patient centered disability measures in Juvenile Idiopathic Arthritis (JIA). OBJECTIVES: To perform a systematic review on the effects of MTX on functional ability, range of motion, quality of life, overall well-being and pain for patients with JIA. SEARCH STRATEGY: The Cochrane Controlled Trials Register (CCTR) and MEDLINE were searched up to March 2001, using the search strategy sensitive for randomised controlled trials, used by the Cochrane Collaboration. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials comparing MTX against placebo or standard care in patients with Juvenile Idiopathic Arthritis (JIA) were selected. DATA COLLECTION AND ANALYSIS: Two reviewers (TT, JN) determined the studies to be included in this review and extracted the data of patient centered disability measures. The data were pooled using standardized mean differences (SMD) for limited joint range score, number of joints with swelling, and number of joints with pain on motion. Physicians global assessment and parents global assessment were evaluated with pooled odds ratios (OR). MAIN RESULTS: Only two studies with a total 165 JIA patients under 18 years of age were included in this review. For JIA patients, MTX therapy had small to moderate effects on patients centered disability. The effect on joint range of motion, number of joints with pain and swelling and parent's assessment of disease activity showed a relative percentage improvement from 3 to 18% greater with MTX than with placebo. REVIEWER'S CONCLUSIONS: Current evidence suggests that MTX does not have clinically significant effects (>20%) on patient centered disability measures in JIA patients.
10813295 The epidemiology of psoriatic arthritis in Olmsted County, Minnesota, USA, 1982-1991. 2000 May OBJECTIVE: To determine the incidence, prevalence, and outcomes of psoriatic arthritis (PsA) in a geographically defined community. METHODS: Using the Rochester Epidemiology Project computerized medical record system, we screened all records of Olmsted County, Minnesota, residents with any diagnosis consistent with psoriasis and/or PsA made between January 1, 1982 and December 31, 1991. Medical records were reviewed using a pretested data collection form. Only those cases of psoriasis where the diagnosis was confirmed by a dermatologist were included. PsA was defined as inflammatory arthritis associated with a definite diagnosis of psoriasis. All identified cases were followed until death, migration from the county, or January 1, 1992. Cases with seropositive rheumatoid arthritis, systemic lupus erythematosus, crystal induced arthritis, Reiter's syndrome, arthritis associated with inflammatory bowel diseases, and inflammatory osteoarthritis were excluded. Clinical characteristics were described using summary statistics. Age and sex adjusted incidence and prevalence rates were calculated. Survival was estimated using the Kaplan-Meier method. RESULTS: We reviewed the records of 1844 patients with a diagnosis of psoriasis. In 1056 of these, the diagnosis was confirmed by a dermatologist. Among these 1056 psoriasis cases, we identified 66 cases (34 female, 32 male) of PsA first diagnosed between 1982 and 1991. The average age and sex adjusted incidence rate per 100,000 US population was 6.59 (95% confidence interval, CI, 4.99, 8.19) and the prevalence on January 1, 1992, was about one per 1000 (95% CI 0.81, 1.21). The average age at diagnosis was 40.7 years. At diagnosis, 91, 3, and 6% of cases had oligoarthritis, polyarthritis, and spondylitis, respectively. Over the 477.8 person-years of followup, 25 developed extraarticular manifestations (enthesitis, n = 15; ocular inflammation, n = 11; urethritis, n = 9), 10 patients received disease modifying antirheumatic drug treatment (methotrexate, n = 7; sulfasalazine, n = 5; intramuscular gold, n = 1; oral gold, n = 1), 3 received corticosteroids, and 5 had surgical interventions (synovectomy, n = 3; arthroplasty, n = 1; other reconstructive surgery, n = 2). Survival was not significantly different from the general population (p = 0.546). CONCLUSION: Unlike results from previous referral based studies, our findings indicate that PsA is a mild, uncommon inflammatory arthritis, not associated with a significant increase in mortality.
9016334 Antirheumatic agents: novel methotrexate derivatives bearing a benzoxazine or benzothiazin 1997 Jan 3 Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H-1,4-benzoxazine were synthesized and tested for in vitro antiproliferative activities against human synovial cells (hSC) and human peripheral blood mononuclear cells (hPBMC) obtained from patients with rheumatoid arthritis and healthy volunteers, respectively. In vivo antiarthritic activities of these derivatives were also evaluated in a rat adjuvant arthritis model. N-[[4-[(2,4-Diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative activities in hSC and hPBMC than MTX in vitro. Antiproliferative activities of N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) and N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68) were comparable to that of MTX in these in vitro assays. Compounds 3b,d (MX-68) significantly suppressed progression of the adjuvant arthritis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In addition, 3d (MX-68) completely suppressed this progression at the dose of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a process which may be responsible for the associated side effects of MTX. These results suggest that 3d (MX-68) is a potent and safe candidate antirheumatic agent, absent of the side effects of MTX.
9805178 Sulphasalazine in the treatment of children with chronic arthritis. 1998 The aim of this study was to investigate the efficacy and toxicity of sulphasalazine (SASP) in the treatment of children with chronic arthritis. The medical records of 36 children (25 boys, 11 girls) who received SASP for the treatment of chronic arthritis were reviewed. Twenty-one patients had juvenile spondyloarthropathies (JSA) (eight juvenile ankylosing spondylitis (JAS), 13 undifferentiated JSA (uJSA) and 15 had juvenile rheumatoid arthritis (JRA). The patients received SASP therapy for a mean of 2.5 years (range 3 weeks to 8.1 years). Clinical and laboratory data were reviewed retrospectively to determine the effects of treatment. A clinically significant response occurred in 23 (64%) children: remission in 14 (39%) (JRA 5, JSA 9) and improvement (25% reduction in joint count) in nine (25%) (JRA 4, JSA 5). There was no difference in response rate between JRA and JSA patients (p = 0.11), but the time to remission was shorter in JSA patients (mean 5 months) than in JRA patients (mean 25 months) (p = 0.024). Twelve of the 36 patients discontinued non-steroidal anti-inflammatory drugs, and six of eight patients discontinued prednisolone. A significant fall in erythrocyte sedimentation rate and rise in haemoglobin occurred in SASP-treated patients (p < 0.005) comparing most recent results with pretreatment levels. Side-effects occurred in four of 36 patients (11%); only one patient who had persisting severe diarrhoea required discontinuation of SASP. It was concluded that SASP appears to be effective and safe in the treatment of JRA and JSA patients. As a second-line agent, SASP is the drug of first choice for patients with JSA; for JRA patients SASP may be a useful, possibly less toxic alternative to methotrexate.
10382002 Pediatric case of accidental oral overdose of methotrexate. 1999 Jul Methotrexate is a chemotherapy antimetabolite, folic acid antagonist, that inhibits the enzyme dihydrofolate reductase resulting in decreased levels of tetrahydrofolate in the cells. This in turn blocks synthesis of thymidylate, a nucleotide necessary for DNA synthesis. It is readily absorbed from the gastrointestinal tract. Toxicity from overdose can affect multiple organ systems including bone marrow, liver, intestinal tract, kidneys, lungs, skin, and blood vessels, resulting in death in severe cases. Methotrexate is widely used to treat neoplastic disease, dermatologic disorders (psoriasis), and rheumatologic disorders (severe rheumatoid arthritis). As its indications for use increase, more accidental overdoses can be expected. We present the treatment and clinical course of one such case, that of a 2-year-old who accidentally took her grandmother's arthritis pills. Her initial serum level was 10 times greater than that needed to cause toxicity. She was treated with gastric lavage, activated charcoal, leucovorin rescue, and ICU admission. Her clinical course was unremarkable, and the only evidence of toxicity was a mild elevation in a liver-associated enzyme that resolved without any clinical sequela. Leucovorin at a dose equal to or greater than the possible ingestion should be given as soon as possible in methotrexate overdoses.
10728760 Reversal of the antiinflammatory effects of methotrexate by the nonselective adenosine rec 2000 Mar OBJECTIVE: Weekly low-dose methotrexate (MTX) remains the mainstay of second-line therapy for rheumatoid arthritis (RA). We have previously reported that adenosine, acting at specific receptors on inflammatory cells, mediates the antiinflammatory effects of MTX in both in vitro and in vivo models of acute inflammation, but the mechanism by which MTX suppresses the chronic inflammation of arthritis remains controversial. The present study was undertaken to further investigate the means by which adenosine mediates the antiinflammatory effects of MTX. METHODS: The effects of 2 nonselective adenosine receptor antagonists, theophylline and caffeine, were examined, using the rat adjuvant arthritis model of RA. These agents were given alone and in conjunction with MTX, and arthritis severity was assessed clinically, radiologically, and histologically. Since rodent adenosine A3 receptors are not blocked by theophylline, selective A1, A2A, and A2B receptor antagonists were tested as well. RESULTS: Control animals developed severe arthritis, which was markedly attenuated by weekly treatment with MTX (0.75 mg/kg/week). Neither theophylline alone nor caffeine alone (each at 10 mg/kg/day) significantly affected the severity of the arthritis, but both agents markedly reversed the effect of MTX as measured by a severity index, hindpaw swelling, and hindpaw ankylosis. Radiographic and histologic analyses confirmed these observations. Neither A1, A2A, nor A2B receptor antagonists affected the capacity of MTX to ameliorate inflammation in adjuvant arthritis. CONCLUSION: These results provide strong evidence that adenosine mediates the antiinflammatory effects of MTX in this model of RA. Moreover, the findings suggest that abstinence from caffeine, a ubiquitous food additive and medication, may enhance the therapeutic effects of MTX in RA.
11669177 Juvenile idiopathic polyarticular arthritis and IgA deficiency in the 22q11 deletion syndr 2001 Oct Five patients with the 22q11 deletion syndrome (velocardiofacial syndrome) developed chronic inflammatory polyarticular arthritis. These new cases add to 8 previously reported and confirm the association. The arthritis in all cases was moderate to severe, but at least partially responsive to methotrexate and/or corticosteroids, and was clinically indistinguishable from juvenile idiopathic arthritis (JIA). Analysis of the total 13 patients indicates that 2 are rheumatoid factor positive, 6 are antinuclear antibody positive, 5 have subtle T cell deficiencies, and 6 have hypergammaglobulinemia. Of particular interest is the occurrence of IgA deficiency in 4 patients, including 2 from our own series. Although IgA deficiency is seen in both JIA (2-4%) and 22q11 deletion syndrome (2-4%), the prevalence of low IgA in this series (31%) is much greater than expected. This phenomenon and the true association of inflammatory arthritis and a chromosome deletion disorder provides further evidence of important genetic factors in the pathogenesis of JIA.
10458088 Methotrexate nodulosis. 1999 Jul Methotrexate (MTX) nodulosis in patients with rheumatoid arthritis treated with MTX has become a well recognized phenomenon. It has not been described in patients receiving MTX for treatment of other diseases, e.g., dermatological or malignant diseases. Recently, MTX nodulosis was described in a patient with psoriasis and arthritis. The pathophysiology and treatment of MTX nodulosis are yet unsettled. We experienced a case with dermatomyositis who developed multiple subcutaneous nodules after treatment with MTX. In our patient, numerous, small, symmetrically distributed, grouped subcutaneous nodules were seen on a V-shaped area of the anterior chest, both axillary areas, and the medial sides of both upper arms and thighs. We histopathologically examined a nodule and started treatment with hydroxychloroquine after discontinuation of MTX. The histopathology revealed septal panniculitis, and the nodules have been under regression. MTX nodulosis may be a drug-specific phenomenon. Discontinuation of MTX and replacement with hydroxychloroquine are recommended in severe cases. Awareness of this entity is important for diagnosing and treating cases of multiple nodules developing after the administration of MTX, which is widely used for many dermatological diseases.
11687174 Methotrexate for treating juvenile idiopathic arthritis. 2001 BACKGROUND: In both adult rheumatoid arthritis (RA) and juvenile arthritis, the focus has shifted from 'inflammation parameters' to more patient centered disability outcomes. In RA this resulted in the development of the Outcome Measures in Arthritis Clinical Trials (OMERACT), and in juvenile arthritis the Pediatric Rheumatology International Trials Organization (PRINTO) core set. This PRINTO-core set was established using a combination of statistical and consensus formation techniques. This core set contains a number of patient centered disability measures. This review systematically searched the available literature and reports the available evidence of efficacy of MTX, with special focus on patient centered disability measures in Juvenile Idiopathic Arthritis (JIA). OBJECTIVES: To perform a systematic review on the effects of MTX on functional ability, range of motion, quality of life, overall well-being and pain for patients with JIA. SEARCH STRATEGY: The Cochrane Controlled Trials Register (CCTR) and MEDLINE were searched up to March 2001, using the search strategy sensitive for randomised controlled trials, used by the Cochrane Collaboration. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials comparing MTX against placebo or standard care in patients with Juvenile Idiopathic Arthritis (JIA) were selected. DATA COLLECTION AND ANALYSIS: Two reviewers (TT, JN) determined the studies to be included in this review and extracted the data of patient centered disability measures. The data were pooled using standardized mean differences (SMD) for limited joint range score, number of joints with swelling. The number of joints with pain on motion were evaluated using weighted mean differences (WMD). Physicians global assessment, parents global assessment and withdrawals due to efficacy and side effects were evaluated with pooled odds ratios (OR). MAIN RESULTS: Only two studies with a total 165 JIA patients under 18 years of age were included in this review. For JIA patients, MTX therapy had small to moderate effects on patient centered disability outcomes. The effect on joint range of motion, number of joints with pain and swelling and physician's and parent's assessment of disease activity showed a relative percentage improvement from 3 to 23% greater with MTX than with placebo. REVIEWER'S CONCLUSIONS: Current evidence suggests that MTX does have minimal clinically significant effects (>20%) on patient centered disability measures in JIA patients.
9279889 Effect of vehicles and penetration enhancers on the in vitro and in vivo percutaneous abso 1997 Aug PURPOSE: Low-dose methotrexate (MTX) is approved for the treatment of recalcitrant rheumatoid arthritis (RA). The objective of this study was to determine the effect of vehicles and penetration enhancers on the percutaneous absorption of MTX and its analog edatrexate (EDAM), and develop transdermal (TD) delivery systems of the drugs for the treatment of RA. METHODS: From previously published pharmacokinetic parameters with low-dose MTX therapy, and considering a 50 cm2 diffusional area, the target steady state in vitro TD flux for MTX was calculated to be 35 micrograms/cm2/hr. Modified Franz diffusion chambers and hairless mouse skin were used for in vitro skin permeation studies. Hairless mice were used for in vivo studies. Delivered amounts of MTX and EDAM were determined by assaying the receiver phase fluid (or blood) with validated reversed phase HPLC methods. RESULTS: Intrinsic partition coefficient of MTX was low (log P = -1.2). Target MTX fluxes of > or = 35 micrograms/cm2/hr were achievable only with 1-15% (v/v) Azone in propylene glycol (PG). Flux of EDAM (85 micrograms/cm2/hr) was higher than MTX from an isopropyl alcohol (IPA)-5% (v/v) Azone system. Clinically significant steady state in vivo blood concentration of MTX and EDAM was achieved using delivery systems containing > or = 2.5% Azone in PG. Area under the drug concentration-time curves (AUC0-24 hr) for MTX were 2379 and 3534 ng*hr/ml from PG-2.5% Azone and PG-7.5% Azone systems respectively. AUC0-24 hr of EDAM was 6893 ng*hr/ml using a PG-2.5% Azone system. CONCLUSIONS: Results of this study show the feasibility of using a transdermal delivery system of MTX and EDAM for the treatment of rheumatoid arthritis.
11407090 Infliximab in the treatment of adult Still's disease refractory to conventional therapy. 2001 May In this study we evaluated the efficacy of Infliximab in the treatment of adult Still's disease (ASD) refractory to conventional therapy. Three patients with chronic and active ASD unresponsive to corticosteroids and methotrexate were given intravenous Infliximab infusions at a dosage of 3 mg/kg at weeks 0, 2, 6 and then once every 8 weeks. Methotrexate was maintained in all cases at a dosage of 15 mg/week, whereas the prednisone dose was modified according to disease activity. The follow-up lasted 50 weeks and disease activity improved in all cases during Infliximab therapy. Two patients presented arthralgias and sore throat at 20 and 28 weeks, that was rapidly controlled by Infliximab reinfusion every 4 weeks. One patient relapsed at 18 weeks and dropped out at 22 weeks due to an urticarioid rash after the beginning of the fifth infusion. Infliximab may be effective in the treatment of relapse of ASD refractory to conventional therapy and requiring continuous high dose corticosteroid medication. Further studies are needed to evaluate the long-term safety, efficacy and the optimal schedule of infusion.
9251892 The mechanisms of action of disease-modifying antirheumatic drugs: a review with emphasis 1997 Aug 1. Rheumatoid arthritis (RA) is probably the most common source of treatable disability. A major problem in modern rheumatology is that the mechanism(s) of action of the currently used disease-modifying antirheumatic drugs (DMARDs) remain unclear. Many of these drugs entered rheumatology mainly through clinical intuition and have been used for decades. 2. The former T-cell-centered paradigm of rheumatoid inflammation has given way to a model of inflammation highlighting the macrophage and its proinflammatory cytokines. In particular, tumor necrosis factor alpha (TNF-alpha) has gained prominence as a central proinflammatory mediator in RA, and antibodies against TNF-alpha have been successfully used in patients with RA. 3. This review will summarize the recent advances in determining the mechanisms of action of the currently used DMARDs, with particular emphasis on their effects on the induction of TNF-alpha and interleukin 1 (IL-1) in mononuclear phagocytes. Although some DMARDs, such as auranofin, antimalarials and tenidap, act as inhibitors of the induction of these cytokines in monocytes or macrophages or both, other drugs, such as methotrexate, D-penicillamine and aurothiomalate, do not seem to affect either TNF-alpha or IL-1. 4. The drugs' effects on proinflammatory cytokine induction are correlated to those on other macrophage responses.
9256612 [A refractory case of adult-onset Still's disease]. 1997 Jun We report here a case of adult-onset Still's disease (AOSD), who finally responded to a combination of cyclophosphamide (CPA) and gold sodium thiomalate (GST) after two years of active disease. A 23-year-old man having continuous high fever with skin rash, polyarthralgia and increased serum ferritin, was diagnosed as AOSD, and oral corticosteroid was initially effective. His symptoms recurred one year later without clinical improvement to increased dosage of steroid. He was admitted to our hospital with pericarditis and pleural effusion but did not respond to either intravenous (i.v.) pulse steroid therapy, methotrexate (MTX) or high dose i.v. gamma-globulin. He was partly responsive to monthly i.v. injection of CPA, but clinical symptoms did not completely subside and hyperferritinemia persisted. GST, initiated in combination with CPA, however, was successful to induce complete remission. MTX has recently been reported to be efficacious to steroid-resistant AOSD, but CPA and gold compounds might be useful to refractory case of AOSD.
9212993 Z-100, extracted from Mycobacterium tuberculosis strain Aoyama B, inhibits the development 1997 Jun We evaluated the effects of Z-100, extracted from human type Mycobacterium tuberculosis strain Aoyama B, on collagen-induced arthritis (CIA) in mice. One hundred thirty-five DBA/1J mice, 8 weeks of age, were assigned to 9 groups and immunized with bovine type II collagen (CII) or CFA. From the next day, Z-100 at doses of 0.004, 0.04, or 0.4 mg/kg B.W./d for 48 d was intradermally injected into the tail base. Methotrexate (MTX) at daily doses of 0.1, 0.3, or 1.0 mg/kg B.W. and cyclophosphamide (CY) at a daily dose of 5 mg/kg B.W. were used as reference drugs. The effects of these drugs on CIA mice were evaluated in terms of the incidence of CIA, the arthritis index (AI), and hind paw edema, after which the animals were sacrificed at 49 d, and both anti-CII antibody titer and delayed-type hypersensitivity (DTH) reaction were measured. In the arthritic control groups, the AI and hind paw edema were significantly increased after the second immunization on day 28. The anti-CII antibody titer and DTH reaction were significantly increased compared to normal mice on day 49. Z-100 significantly inhibited the AI at a dose of 0.4 mg/kg/d on day 49, and suppressed the incidence of both CIA and hind paw edema. Increases in both anti-CII antibody titer and DTH reaction in CIA mice were prevented by treatment with Z-100 at 0.4 mg/kg/d. MTX, in a dose-dependent manner, and CY, at a dose of 5 mg/kg/d, inhibited the incidence of CIA, AI, hind paw edema, anti-CII antibody titer and DTH reaction in CIA mice. Z-100 at a dose of 0.4 mg/kg was as effective as MTX was at a dose of 0.3 mg/kg against the DTH reaction, and it had no side effects. These results suggest the usefulness of Z-100 in patients with chronic rheumatoid arthritis.
11407702 Etanercept therapy in children with treatment-resistant uveitis. 2001 Jun OBJECTIVE: To evaluate the safety and efficacy of the tumor necrosis factor fusion protein etanercept in children with treatment-resistant uveitis. METHODS: Ten children with chronic active uveitis (7 girls and 3 boys, mean age 7.5 years [range 3-12 years]) were enrolled in this prospective study. In 7 children, uveitis was associated with pauciarticular juvenile rheumatoid arthritis. Five children were antinuclear antibody positive. All patients had failed previous therapy with topical steroids and methotrexate and/or cyclosporine. All were treated with etanercept at a dosage of 0.4 mg/kg twice weekly for the first 3 months, and then, if eyes did not improve, with 25 mg twice weekly (mean 1.1 mg/kg) for at least 3 additional months. RESULTS: At the beginning of the trial, uveitis affected 18 eyes in the 10 children. Within 3 months, 10 of 16 affected eyes (63%; P = 0.017) showed a rapid decrease in anterior chamber cell density, including remission of uveitis in 4 eyes. In children with visual acuity of less than 20/25, 4 of 10 eyes (40%) improved. An exacerbation of uveitis during etanercept therapy occurred in only 1 child (1 of 14 eyes [7%]). Other ocular outcome parameters, such as intraocular pressure, synechia formation, and lens clarity, remained unchanged. Following a dosage increase to an average of 1.1 mg/kg after 3 months in 7 children, no further improvement was noted. CONCLUSION: Our data suggest that etanercept injected subcutaneously twice a week has a beneficial effect on treatment-resistant chronic uveitis in children. Further controlled studies with etanercept in systemic or topical form are necessary to confirm its efficacy and optimal mode of administration.
10544838 Effects of PEGylated soluble tumor necrosis factor receptor type I (PEG sTNF-RI) alone and 1999 Sep OBJECTIVE: To determine the potential combination benefit of treatment with PEG sTNF-RI and methotrexate in adjuvant arthritic rats. METHODS: Lewis rats with adjuvant arthritis were treated by sc injections of either 3.0 or 0.3 mg/kg PEG sTNF-RI on days 9, 11, and 13 of adjuvant arthritis. The effects of PEG sTNF-RI treatment alone were compared to treatment with daily oral methotrexate (0.075, 0.06 or 0.045 mg/kg) or methotrexate in combination with PEG sTNF-RI. Efficacy was monitored by volume measurement of ankle joints, final paw weights and histologic evaluation with particular emphasis on bone lesions. RESULTS: Treatment with 3.0 or 0.3 mg/kg PEG sTNF-RI alone resulted in 52% or 28% inhibition, respectively, of paw swelling as assessed by final paw weight. Treatment with methotrexate at either 0.075, 0.06, or 0.045 mg/kg gave 84%, 51% or 18% inhibition and combination treatment resulted in additive inhibitory effects. Histologic evaluation of ankle joints demonstrated 68% or 25% inhibition of bone resorption with PEG sTNF-RI alone at 3.0 or 0.3 mg/kg. Treatment with 0.075, 0.06 or 0.045 mg/kg methotrexate resulted in 98%, 76% or 40% inhibition of bone resorption. Additive benefit was best seen with the lower doses of methotrexate. CONCLUSION: Combination therapy with PEG sTNF-RI and methotrexate results in additive benefit, with the final result being excellent inhibition of all arthritis parameters. Data from these studies supports the clinical investigation of the use of combination therapy of PEG sTNF-RI and methotrexate in rheumatoid arthritis patients.
9058664 Salazosulfapyridine suppresses chondrocyte mediated degradation induced by interleukin 1be 1997 Mar OBJECTIVE: To investigate the effects of salazosulfapyridine (SASP) and methotrexate (MTX) on interleukin (IL)-1beta treated rabbit chondrocytes. METHODS: Normal rabbit chondrocytes were cultured to confluency. IL-1beta was added to serum-free culture medium in the presence or absence of SASP or MTX. After 2 days' incubation, the effects were evaluated from the responses of metalloproteinases, glycosaminoglycan (GAG), and prostaglandin E2 (PGE2). RESULTS: SASP and MTX suppressed GAG and collagenase release into the culture medium from IL-1beta stimulated rabbit chondrocytes in a dose dependent manner. Only SASP suppressed stromelysin and PGE2 release. CONCLUSION: SASP may have a protective effect on cartilage degradation of patients with rheumatoid arthritis.
11729668 [A case of chronic erosive polyarthritis which developed 14 years after an intestinal bypa 2001 Oct A 38-year-old female patient developed the symptoms and signs of arthritis in the right tarsal joint for the first time after 14 asymptomatic years following an ileo-colic intestinal bypass operation which had been performed as an emergency procedure for acute ileus due to intestinal adhesions caused by the previous abdominal surgery. Her arthritis took a progressively severe course thereafter, primarily involving the joints of both lower extremities, and 13 years after the onset of symptoms she still continued to have active polyarthritis. However, no concomitant skin lesions of any form had been recognized throughout the course of the arthritis. On the articular radiographs erosive changes were evident in the right tarsal joints and also in the MTP joints of both big toes. Laboratory examinations of the serum revealed negative results for rheumatoid factor, circulating immune-complexes, anti-nuclear antibodies, and anti-DNA antibodies, while the serum level of CRP as well as the erythrocyte sedimentation rate were elevated. Other routine laboratory tests were all unremarkable, and neither HLA-B 27 nor HLA-DR 4 were positive. Therapeutic drug regimens consisting of NSAIDs, oral as well as intraarticular steroids, DMARDs, methotrexate, and combinations of these drugs were unsuccessful in controlling the severe symptoms of the arthritis. In view of this, a revision operation of intestinal bypass was performed 13 years after the onset of the arthritis. After the revision the severe pain of the arthritis began to subside gradually, and 1 year and 6 months later the patient achieved complete remission of the arthritis, and her CRP and ESR values returned to normal.
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