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ID PMID Title PublicationDate abstract
9071820 Benefit of simultaneous rhG-CSF and methylprednisolone 'pulse' therapy for methotrexate-in 1997 Feb A 74-year-old female with seropositive rheumatoid arthritis developed severe bone marrow failure after the treatment with very low-dose methotrexate (5 mg/week for 3 weeks). Hematological data showed severe pancytopenia with 0% neutrophils and bone marrow disclosed thoroughly hypocellular marrow. Shortly after the treatment with simultaneous rhG-CSF and methylprednisolone 'pulse' therapy, pancytopenia was ameliorated and bone marrow examination revealed hypercellular marrow with increasing maturation of hematopoietic components. Hematological parameters were maintained within the normal range with a low dose of prednisolone.
11327241 High dose chemotherapy followed by autologous peripheral blood stem cell transplantation o 2001 Apr OBJECTIVE: To evaluate the effect of high dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) in comparison to conventional pharmacological therapy in the treatment of patients with refractory, progressively erosive rheumatoid arthritis (RA). METHODS: Decision analysis using a Markov model with a 5.5 year time horizon. Probabilities of transition towards 5 different health states, ranging from 70% improvement to death, were derived from published case reports, patient series, and expert panels. Quality of life (QOL) estimates were obtained from 2 RA clinical trials. Patients were hypothetical cohorts of 50-year-old female patients with progressively erosive, active RA, who failed treatment with methotrexate, combination therapy, and tumor necrosis factor blocking agents. Interventions were HDC + ASCT versus conventional pharmacological treatment with a (combination) therapy of disease modifying antirheumatic drugs. As main outcome measures, we included the number of quality adjusted life years (QALY) after HDC + ASCT compared to conventional therapy. Sensitivity analysis was performed to investigate the influence of treatment related mortality (TRM) and the influence of QOL during HDC + ASCT, and to assess the minimal desired effectiveness of HDC + ASCT for a given TRM of 1% and 10%. RESULTS: HDC + ASCT and conventional pharmacological treatment were equally effective in the base-case analysis (3.48 vs 3.46 QALY). A TRM of less than 3.3% favored HDC + ASCT as the preferred treatment. The analysis showed that when TRM was set at 1%, a relatively short period of efficacy was sufficient to remain the preferred strategy, whereas a TRM of 10% would require a sustained response for several years. CONCLUSION: This model predicted equally favorable effects of HDC + ASCT and conventional therapy in the treatment of refractory RA in the base-case. The minor differences in terms of QALY seem to indicate that clinical decision making should be guided by patient preferences. However, better clinical efficacy might be achieved by adaptation of the treatment regimen of HDC + ASCT and patient selection. The model supports the need for randomized clinical trials and may contribute to an optimal study design.
9415629 Differences in the use of second-line agents and prednisone for treatment of rheumatoid ar 1997 Dec OBJECTIVE: To compare the use of methotrexate (MTX), intramuscular (i.m.) gold, hydroxychloroquine, and prednisone for rheumatoid arthritis (RA) treatment among patients managed by rheumatologists and nonrheumatologists. METHODS: Multiple regression analysis to estimate the likelihood of starting treatment and response to treatment for patients managed by rheumatologists and nonrheumatologists. All regression analyses were adjusted for patient demographic and clinical characteristics. RESULTS: Therapy with all agents studied was initiated more frequently for patients with RA with at least some contact with rheumatologists during the year than for those managed strictly by nonrheumatologists. The adjusted odds ratios for starts on these medications ranged from 1.14 for im gold to 15.11 for MTX for patients managed by rheumatologists compared to those managed by nonrheumatologists. However, due to the low frequency of initiation of treatment with most of these drugs for patients managed strictly by nonrheumatologists, only the odds ratio for prednisone reached statistical significance (OR = 2.94, p = 0.0082). In the year after initiation of therapy with these agents, patients managed by rheumatologists experienced better response to treatment than those managed by nonrheumatologists. These differences were statistically significant for MTX (p = 0.0447) and nearly significant for im gold (p = 0.0597). CONCLUSION: These results provide evidence of systematic differences in the propensity of rheumatologists and nonrheumatologists to initiate therapy with these antirheumatic drugs. If the observed differences in initial response to treatment translate into substantial differences in longterm outcomes, then these results suggest that the welfare of patients with RA may be jeopardized by the current trend toward primary care and restricted access to rheumatologists.
11056662 Kinesin-like protein CENP-E is upregulated in rheumatoid synovial fibroblasts. 1999 Articular destruction by invading synovial fibroblasts is a typical feature in rheumatoid arthritis (RA),. Recent data support the hypothesis that key players in this scenario are transformed-appearing synovial fibroblasts at the site of invasion into articular cartilage and bone. They maintain their aggressive phenotype toward cartilage, even when first cultured and thereafter coimplanted together with normal human cartilage into severe combined immunodeficient mice for and extended period of time. However, little is known about the upregulation of genes that leads to this aggressive fibroblast phenotype. To inhibit this progressive growth without interfering with pathways of physiological matrix remodelling, identification of pathways that operate specifically in RA synovial fibroblasts is required. In order to achieve this goal, identification of genes showing upregulation restricted to RA synovial fibroblasts is essential. AIMS: To identify specifically expressed genes using RNA arbitrarily primed (RAP)-polymerase chain reaction (PCR) for differential display in patients with RA. METHODS: RNA was extracted from cultured synovial fibroblasts from 10 patients with RA, four patients with osteoarthritis (OA), and one patient with psoriatic arthritis. RAP-PCR was performed using different arbitrary primers for first-strand and second-strand synthesis. First-strand and second-strand synthesis were performed using arbitrary primers: US6 (5'-GTGGTGACAG-3') for first strand, and Nuclear 1+ (5'ACGAAGAAGAG-3'), OPN28 (5'GCACCAGGGGG-3'), Kinase A2+(5'-GGTGCCTTTGG-3') and OPN24 (5'AGGGGCACCA-3') for second strand synthesis. PCR reactions were loaded onto 8 mol/l urea/6% polyacrylamide-sequencing gels and electrophoressed. Gel slices carrying the target fragment were then excised with a razor blade, eluated and reamplified. After verifying their correct size and purity on 4% agarose gels, the reamplified products derived from the single-strand confirmation polymorphism gel were cloned, and five clones per transcript were sequenced. Thereafter, a genbank analysis was performed. Quantitative reverse transcription PCRj of the segments was performed using the PCR MIMIC technique. In-situ expression of centromere kinesin-like protein-E (CENP-E) messenger (m)RNA in RA synovium was assessed using digoxigenin-labelled riboprobes, and CENP-E protein expression in fibroblasts and synovium was performed by immunogold-silver immunohistochemistry and cytochemistry. Functional analysis of CENP-E was done using different approaches (eg glucocorticoid stimulation, serum starvation and growth rate analysis of synovial fibroblasts that expressed CENP-E). RESULTS: In RA, amplification of a distinct PCR product suitable for sequencing could be observed. The indicated complementary DNA fragment of 434 base pairs from RA mRNA corresponded to nucleotides 6615-7048 in the human centromere kinesin-like protein CENP-E mRNA (GenBank accession No. emb/Z15005). The isolated sequence shared greater than 99% nucleic acid (P=2.9e(-169)) identify with the human centromere kinesin-like protein CENP-E. Two base changes at positions 6624 (A to C) and 6739 (A to G) did not result in alteration in the amino acid sequence, and therefore 100% amino acid identity could be confirmed. The amplification of 10 clones of the cloned RAP product revealed the presence of CENP-E mRNA in every fibroblast culture examined, showing from 50% (271.000 +/- 54.000 phosphor imager arbitrary units) up to fivefold (961.000 +/- 145.000 phosphor image arbitrary units) upregulation when compared with OA fibroblasts. Neither therapy with disease-modifying antirheumatic drugs such as methotrexate, gold, resochine or cyclosporine A, nor therapy with oral steroids influenced CENP-E expression in the RA fibroblasts. Of the eight RA fibroblast populations from RA patients who were receiving disease-modifying antirheumatic drugs, five showed CENP-E upregulation; and of the eight fibroblast populations from RA patients receiving steroids, four showed CENP-E upregulation. Numerous synovial cells of the patients with RA showed a positive in situ signal for the isolated CENP-E gene segment confirming CENP-E mRNA production in rheumatoid synovium, whereas in OA synovial tissue CENP-E mRNA could not be detected. In addition, CENP-E expression was independent from medication. This was further confirmed by analysis of the effect of prednisolone on CENP-E expression, which revealed no alteration in CENP-E mRNA after exposure to different (physiological) concentrations of prednisolone. Serum starvation also could not suppress CENP-E mRNA completely. DISCUSSION: Since its introduction in 1992, numerous variants of the differential display method and continuous improvements including RAP-PCR have proved to have both efficiency and reliability in examination of differentially regulated genes. The results of the present study reveal that RAP-PCR is a suitable method to identify differentially expressed genes in rheumatoid synovial fibroblasts. The mRNA, which has been found to be upregulated in rheumatoid synovial fibroblasts, codes for a kinesin-like motor protein named CENP-E, which was first characterized in 1991. It is a member of a family of centromere-associated proteins, of which six (CENP-A to CENP-F) are currently known. CENP-E itself is a kinetochore motor, which accumulates transiently at kinetochores in the G2 phase of the cell cycle before mitosis takes place, appears to modulate chromosome movement and spindle elongation,and is degraded at the end of mitosis. The presence or upregulation of CENP-E has never been associated with RA.The three-dimensional structure of CENP-E includes a coiled-coil domain. This has important functions and shows links to known pathways in RA pathophysiology. Coiled-coil domains can also be found in jun and fos oncogene products, which are frequently upregulated in RA synovial fibroblasts. They are also involved in DNA binding and transactivation processes resembling the situation in AP-1 (Jun/Fos)-dependent DNA-binding in rheumatoid synovium. Most interestingly, these coiled-coil motifs are crucial for the assembly of viral proteins, and the upregulation of CENP-E might reflect the influence of infectious agents in RA synovium. We also performed experiments showing that serum starvation decreased, but did not completely inhibit CENP-E mRNA expression. This shows that CENP-E is related to, but does not completely depend on proliferation of these cells. In addition, we determined the growth rate of CENP-E high and low expressors, showing that it was independent from the amount of CENP-E expression. supporting the statement that upregulation of CENP-E reflects an activated RA fibroblast phenotype. In summary, the results of the present study support the hypothesis that CENP-E, presumably independently from medication, may not only be upregulated, but may also be involved in RA pathophysiology.
11171679 The national database of the German Collaborative Arthritis Centres: II. Treatment of pati 2001 Mar OBJECTIVE: To describe current treatment of patients with rheumatoid arthritis (RA) in German rheumatology. METHODS: Data from the German rheumatological database of 1998, comprising clinical and patient questionnaire data of 12 992 outpatients with RA seen at 24 collaborative arthritis centres in Germany, were analysed. RESULTS: At the time of documentation, 88% of the patients with RA were undergoing disease modifying antirheumatic drug (DMARD) treatment. Methotrexate (MTX) was prescribed to 56% of the patients (61% with seropositive and 45% with seronegative RA). Combination treatment was used in 15%. MTX was the drug of first choice even in patients with up to one year's disease duration (49%), followed by antimalarial drugs (21%). Patients treated by non-rheumatologists within the previous year had received DMARD treatment in only 33% of the cases. In steroid treatment, low doses (< or = 7.5 mg/day) were used by rheumatologists much more often (44%) than higher doses (12%). 16% of the patients had been inpatients during the previous year, with a median length of stay accumulated over the year of 21 days. Together with stays in inpatient rehabilitation, 22% of all patients had had some form of inpatient treatment. Comprehensive measures such as occupational therapy and patient education were prescribed to fewer than 12% of the patients, mostly during their hospital stay. CONCLUSION: German rheumatologists do follow recent recommendations about early and effective treatment. However, there are still deficits in outpatient care with non-medicinal measures like occupational therapy and patient education, which may partly explain the high hospital admission rates.
10685644 Epstein-Barr virus-associated Hodgkin's lymphoma and legionella pneumophila infection comp 2000 Feb We describe the case of a 53-month-old girl with juvenile rheumatoid arthritis (JRA), complicated by the occurrence of Hodgkin's lymphoma and Legionella pneumophila infection during immunosuppressive treatment with methotrexate (MTX) and cyclosporine A (CSA). The girl had received variable anti-inflammatory combination therapy, including MTX for 28 months and CSA for 3 months. Thirty-six months after the onset of arthritis, the girl presented with an enlargement of the lymph nodes of the mediastinum, the hilum of the lungs, and the abdomen. Concomitantly, a diagnosis of Legionella pneumonia was rendered. Autopsy showed Epstein-Barr virus (EBV)-associated nodular sclerosing Hodgkin's lymphoma. The neoplastic cells were positive for CD15, CD 30, and latent membrane protein 1 (LMP 1). The present case is the second reported to occur in a child, and it lends support to the hypothesis that immunosuppressive treatment may contribute to an increased risk of the development of EBV-associated lymphoproliferative disorders (LPD) in pediatric patients suffering from JRA.
11168012 IL-1 beta- and IL-4-induced down-regulation of autotaxin mRNA and PC-1 in fibroblast-like 2001 Jan Autotaxin (ATX) is a 125-kD ectonucleotide pyrophosphate/phosphodiesterase, which was initially isolated and cloned from human melanoma cells as a potent stimulator of tumour cell motility. ATX shows 44% identity to the plasma cell membrane marker PC-1. Recently, we described the decreased expression of ATX mRNA in cultured fibroblast-like synoviocytes (SFC) of patients with RA by interferon-gamma. In this study using a competitive reverse transcriptase-polymerase chain reaction, we show an increased ATX mRNA expression in SFC from patients with RA in comparison with synoviocytes from non-RA patients. The median ATX mRNA amount in SFC of RA patients (440 pg/microg total RNA) was five-fold higher than the expression in synoviocytes from non-RA patients (80 pg/microg total RNA) or foreskin fibroblasts (MRHF cells, 90 pg/microg total RNA). In contrast to the elevated ATX mRNA expression in SFC of patients with RA, we did not measure increased mRNA amounts of PC-1 in these cells. Both the ATX mRNA amount and the 5'-nucleotide phosphodiesterase (PDE) activity of SFC lysate were reduced after treatment of SFC with the cytokines IL-1beta or IL-4. IL-1beta and IL-4 induced a down-regulation of PC-1 mRNA and protein expression in SFC. In SFC treated with transforming growth factor-beta the expression of PC-1 mRNA and protein was increased, whereas no significant effect on ATX mRNA expression was detectable. Pharmacological drugs used in therapy for RA, such as dexamethasone, cyclosporin, methotrexate and indomethacin, did not show a statistically significant effect on either ATX mRNA or PC-1 mRNA expression. Only pentoxifylline suppressed ATX mRNA as well as PC-1 mRNA expression. In conclusion, we show a tight regulation of ATX and PC-1 gene expression by cytokines detectable in the inflamed tissue of RA. Further investigations will deal with the regulation of ATX protein expression as well as with the function of ATX in RA.
9673632 Changing patterns in the use of slow acting antirheumatic drugs for the treatment of rheum 1998 Jun 12 AIM: To report on the changing use of slow acting antirheumatic drugs in the treatment of rheumatoid arthritis by contrasting prescribing patterns in 1990 and 1995. METHOD: Data were extracted from the case notes of 103 outpatients with rheumatoid arthritis. Results were compared with those obtained in 1990 in a survey of 81 patients using identical methods. RESULTS: There was a significant increase in the use of methotrexate between 1990 and 1995, and a marked decrease in the use of auranofin. A new feature was the use of drugs in combination. Methotrexate was the most effective agent and auranofin least effective (p = 0.02). The agent with the highest average toxicity score was D-penicillamine. The long term tolerability of methotrexate was superior, with a median time for remaining on therapy 6.4 times longer than that of the other slow acting antirheumatic drugs (p = 0.01). CONCLUSIONS: Our results suggest that identified trends in the altered use of slow acting antirheumatic drugs for treatment of rheumatoid arthritis are rationally based on the increased use of the most effective agents and decreased use of those with greater toxicity and lesser efficacy.
9489813 Longterm prospective study of methotrexate in rheumatoid arthritis: conclusion after 132 m 1998 Feb OBJECTIVE: To conclude observations of efficacy of longterm methotrexate (MTX) treatment of rheumatoid arthritis (RA). METHODS: Twenty-six patients with RA entered a prospective study of MTX in 1983. The study was completed after 132 months of therapy. RESULTS: Significant improvement (p < 0.001) was noted in the number of painful joints, swollen joints, and physician and patient global assessments. There was 50% improvement in the joint pain index and joint swelling index in > 65% of the patients. A significant reduction in prednisone dose was achieved. Sixteen patients withdrew from the study. Toxicity led to 3 drug related withdrawals of study patients (alopecia 1; pneumonitis 2). At 132 months, 10 patients (38%) had completed the study; 3 patients (11%) discontinued due to MTX toxicity. CONCLUSION: MTX was an effective treatment for RA in this 132 month prospective study.
10520307 [Abdominal actinomycosis after stomach surgery in a patient with long-term rheumatoid arth 1999 Sep 17 HISTORY AND ADMISSION FINDINGS: A 78-year-old woman had a 30-year history of rheumatoid arthritis, of late treated with prednisolone and methotrexate. A week before admission she had first noticed a mass about 3 cm in diameter, at the lower end of a scar from a Billroth II gastric resection for gastric ulcer, performed 4 months before. She reported to have lost 6.5 kg in weight. On admission a moderately mobile, hard mass was palpated on the abdomen. INVESTIGATIONS: Ultrasound and computed tomography revealed a superficial, inhomogenous space-occupying lesion with poorly circumscribed margins. TREATMENT AND COURSE: After two days the skin over the mass became reddened and a laparotomy was performed because an incarcerated herniation was suspected. An abscess and inflammatory adhesions were found in the area of the transverse colon, histologically shown to be a chronic purulent abscess with granular clusters of pathogens indicating actinomycosis. After 3 weeks' treatment with imipenem i.v. the patient became free of symptoms, oral doxycyclin was continued for a further 6 months. CONCLUSION: Actinomycosis should be considered in the differential diagnosis of a tumour of undetermined benignity in the region of the head, chest or abdomen in immunosuppressed patients. This bacterial infection should be thought of especially if the gastrointestinal mucosa has been penetrated by invasive procedures.
10668525 Leflunomide versus methotrexate: a comparison of the European and American experience. 1999 This paper compares and contrasts the results of two major Phase III clinical trials that compared the efficacy and safety of leflunomide, a new disease-modifying antirheumatic drug (DMARD), and methotrexate. In both the American trial (US301) and the multinational trial (MN302), patients with active rheumatoid arthritis (RA) were given either leflunomide (20 mg/day after a loading dose of 100 mg/day for 3 days) or methotrexate (7.5-15 mg/week) for 52 weeks. US301 was also placebo-controlled. Folate supplementation was mandatory in US301 but was given to < 10% of the patients in MN302. In US301, American College of Rheumatology (ACR) 20% response rates and improvement in tender and swollen joints were significantly better than placebo in both treatment groups, but were not significantly different from each other. Both treatments significantly retarded radiographically assessed progression of RA compared to placebo, but the degree of retardation was significantly greater with leflunomide. In MN302, the ACR response rate and improvement in tender and swollen joints with leflunomide were similar to those seen in US301. The ACR response rate and improvements in all efficacy variables with methotrexate were significantly greater than with leflunomide, however. Radiographically assessed disease progression was not statistically different with the two treatments. Use of methotrexate without folate in MN302 was associated with a higher incidence of clinically significant elevations of liver enzyme levels. These results indicate that both leflunomide and methotrexate are effective DMARDs. The symptomatic relief provided by both drugs is similar when they are given with folate supplementation.
11136881 Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthri 2000 Dec OBJECTIVE: To evaluate the toxicity of slow-acting anti-rheumatic drugs (SAARDs) and non-steroidal anti-inflammatory drugs (NSAIDs) in early rheumatoid arthritis. METHODS: Patients were randomized to receive a SAARD-hydroxychloroquine (HCQ; n=120), i.m. gold (n=114) or methotrexate (MTX; n=118)-or a NSAID only (n=67). Patients in the three SAARD groups were allowed to take NSAIDs. Follow-up included 545 patient-years (p-yr). Adverse effects were attributed to specific medications using the Naranjo scoring method. RESULTS: Fifty-five per cent of the patients suffered from adverse effect(s). Adverse effects were most common during i.m. gold therapy (87 per 100 p-yr), which led to permanent discontinuation of this treatment in 31 cases. The incidences of adverse effects that were probably attributable to NSAIDs in patients treated simultaneously with a SAARD were similar for the three SAARD groups. The mean period until the first adverse effect was longer in the MTX group (39 weeks) than in the HCQ group (27 weeks). Baseline clinical and sociodemographic parameters were not predictive of the occurrence of adverse effects. CONCLUSION: No adverse effect could be classified as definitely related to either SAARDs or NSAIDs by the Naranjo scoring method. The incidence of possible adverse effects of NSAIDs and SAARDs was 72 per 100 p-yr, and adverse effects led to permanent discontinuation of the therapy in 56 cases (13%) (31 patients receiving i.m. gold, 12 receiving MTX, 10 receiving HCQ and three receiving NSAID only).
9458200 The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxi 1998 Jan OBJECTIVE: To assess the efficacy of folic acid and folinic acid in reducing the mucosal and gastrointestinal (GI) side effects of low dose methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: A systematic review was carried out using the methods recommended by the Cochrane Collaboration. We used MEDLINE and performed hand searches that included bibliographic references, Current Contents, abstracts of rheumatology meetings, and 4 rheumatology journals to select double blind randomized controlled trials (RCT) in which adult patients with RA were treated with low doses of MTX (< 20 mg/week), concurrently with folic or folinic acid. The quality of the RCT was assessed. The overall treatment effect across trials (reduction in toxicity) was estimated using a fixed effects model. Disease activity was evaluated using standardized mean differences to ensure comparability across outcome measures. Sensitivity analyses were conducted evaluating different doses and the quality of the trials. Costs per month in different countries were compared. RESULTS: Of 11 trials retrieved, 7 met inclusion criteria. The total sample included 307 patients, of which 147 were treated with folate supplementation, 67 patients with folic, and 80 with folinic acid. A 79% reduction in mucosal and GI side effects was observed for folic acid [OR = 0.21 (95% CI 0.10 to 0.44)]. For folinic acid, a clinically but nonstatistically significant reduction of 42% was found [OR = 0.58 (95% CI 0.29 to 1.16)]. No major differences were observed between low and high doses of folic or folinic acid. Hematologic side effects could not be analyzed, since details by patients of each event were not provided. No consistent differences in disease activity variables were observed when comparing placebo and folic acid or folinic acid at low doses; patients receiving high dose folinic acid had increased tender and swollen joint counts. Substantial differences in costs across countries were found; folinic acid was more expensive. CONCLUSION: Our results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems.
10943871 Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment wi 2000 Aug OBJECTIVE: To determine whether a regimen of methotrexate, cyclosporin A, and corticosteroids introduced at onset in poor-prognosis rheumatoid arthritis (RA) can produce a significant improvement in outcome compared with standard monotherapy with sulfasalazine (SSZ). METHODS: Eighty-two consecutive patients presenting with new, untreated RA of less than 12 months' duration who fulfilled criteria for poor long-term outcome were randomized to receive either combination therapy (n = 40) or SSZ alone (n = 42). The primary outcome measures were remission and American College of Rheumatology (ACR) criteria for 20% improvement at 48 weeks. RESULTS: After 48 weeks, the numbers of patients who met the ACR criteria for 20% improvement were not significantly different between the two groups (combination 58% versus SSZ 45%), and similar numbers of patients had persisting clinical remission (approximately 10% both groups). During the first 3 months, there were significantly greater reductions in parameters of disease activity in the combination group. By 24 weeks, the swollen and tender joint counts, C-reactive protein levels, and erythrocyte sedimentation rates had fallen significantly in both groups, with a greater improvement in the swollen and tender joint count in the combination group. At 48 weeks, the radiographic damage score had increased by a median of 1 (range 0-42.5) in the combination group and 1.25 (range 0-72.5) in the SSZ group (P = 0.28; although there were significant differences in the scores for the right hand). There were significantly fewer withdrawals due to lack of efficacy in the combination group than in the SSZ group (1 of 40 versus 10 of 42; P = 0.007). In the combination group, dose reduction was needed in 22.5% because of hypertension and in 22.5% because of elevated creatinine levels. Over 48 weeks, serum creatinine increased in both groups, but particularly in the combination arm. CONCLUSION: In poor-prognosis RA patients, "aggressive" combination therapy led to more rapid disease suppression but did not result in significantly better ACR response or remission rates. This suggests that in poor-prognosis disease, an approach based on identifying patients with poor treatment responses before extra therapy is added ("step-up" approach) may be more appropriate than the use of combination therapy in all patients from the outset.
9712088 Longterm combination therapy of refractory and destructive rheumatoid arthritis with metho 1998 Aug OBJECTIVE: To evaluate tolerability and efficacy of combination therapy with methotrexate (MTX)/parenteral gold or MTX/other disease modifying antirheumatic drug (DMARD, d-penicillamine or chloroquine) in comparison with MTX monotherapy in patients with longstanding destructive active rheumatoid arthritis (RA). METHODS: In an open prospective trial all consecutive MTX-naive patients with active RA starting MTX treatment alone or in combination between January 1980 and December 1987, after failing one or more DMARD, were followed at regular intervals up to 108 months. Evaluations included the number of swollen joints (0-32), grip strength, patient assessment of pain and mobility, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and hemoglobin. Group 1, treated with MTX monotherapy (n = 97), was compared with Group 2, with combination therapy MTX/parenteral gold (n = 126) and Group 3 with MTX + other DMARD (n = 48). RESULTS: There were no significant differences between the groups in mean age (59/57/56 yrs), disease duration (9.6/7.7/8.3 yrs), seropositivity (80/88/82%), or ACR anatomical disease stage (2/3 in stage III and IV). The number of swollen joints (16.8/19.3/16.1 of 32) and the CRP (4.4/5.1/4.7 mg/dl) was significantly greater in Group 2; other disease activity variables were not significantly different. The mean MTX dose at baseline (mostly parenteral) was 16.8/17.0/12.8 mg and could be reduced to around 12 mg (predominantly oral) in the 3 groups. Frequency of adverse events (80/83/88%), nature of clinical (nausea, hair loss, stomatitis) and laboratory (liver enzyme elevation, slight proteinuria) side effects, and withdrawal rate for side effects (20.6/15.0/12.5%) were not significantly different between the groups. After 5 years 54/54/80% of patients continued their treatment. All efficacy variables improved significantly (p < 0.001) in all groups without significant intergroup difference. Improvement > 50% in the ESR was achieved in 63/68/41% and in the swollen joint count in 70/85/48% of patients after 3 years. The number of patients taking oral steroids decreased from 63/59/65% to 22/31/48% after 3 years. In half the patients hemoglobin increased by at least 1 g/dl. CONCLUSION: Combination therapy of MTX with parenteral gold or other DMARD is effective in reducing clinical and biochemical disease activity in patients with longstanding destructive RA with no greater risk of toxicity compared with MTX alone; our study however, did not show clear advantages of combination therapy versus monotherapy for effectiveness.
10081378 [Methotrexate and folates in rheumatoid arthritis]. 1999 Feb 10 The efficacy of weekly low-dose methotrexate treatment of rheumatoid arthritis is well documented. Efficacy and adverse events are both dose dependent, and side effects rather than lack of response are the main reason for discontinuing therapy. Several adverse effects appear to be related to folate deficiencies, and are largely due to the antifolate properties of methotrexate. In order to diminish side effects without compromising drug efficacy, clinical trials have been performed using folic acid or folinic acid concomitantly with methotrexate. Important to this achievement are both the timing of folate supplementation and the weekly folate-to-methotrexate ratio. Considering these and other factors, an individually adjusted supply of folic acid is proposed. For several patients a properly balanced diet is sufficient; they do not need additional folate supplements when using methotrexate.
9431590 Inadequate calcium, folic acid, vitamin E, zinc, and selenium intake in rheumatoid arthrit 1997 Dec OBJECTIVES: To determine the adequacy of calcium, folic acid, vitamin E, zinc, and selenium intake in patients with rheumatoid arthritis (RA). METHODS: We conducted an observational study on 48 patients (13 men, 35 women; mean age, 64.5 years) with RA attending a specialty clinic in New Zealand comparing their dietary intake as measured by a 5-day dietary survey with recommended dietary intake (RDI) guidelines. Information on disease activity, functional ability, and drug therapy also was obtained. RESULTS: The percentage of patients who achieved the RDI was 23% for calcium, 46% for folic acid, 29% for vitamin E, 10% for zinc, and only 6% for selenium. Patients on methotrexate had a significantly reduced intake of folic acid as a percentage of RDI (P < .05) compared with those on other therapies. In contrast, dietary intake of iron and protein was largely adequate and unrelated to anemia. CONCLUSIONS: Patients with RA should receive dietary education or supplementation to bring their intake of calcium, folic acid, vitamin E, zinc, and selenium up to the RDI.
11291608 [Five year clinical evaluation of treatment efficacy with methotrexate in patients with rh 2000 May The objective of this study was to determine long term efficacy and safety of low dose methotrexate (MTX) in treatment of rheumatoid arthritis (RA). Thirty patients receiving MTX for RA were prospectively studied over a mean treatment period of 60 months. Standard clinical and laboratory measures of disease activity were assessed by the same investigator at baseline, and at 3, 6, 24, and 60 months. The occurrence of adverse reactions was noted. Initially MTX was given orally 7.5 mg once a week. In the course of the observation the dose ranged between 5 and 15 mg/week. 13 patients (43%) completed 5-years study. Treatment with MTX was stopped due to adverse events in 4 cases, inefficacy in 7 patients, poor compliance and fear of toxicity in 3 patients and death in 3 patients. The factors related to their death were unrelated in all 3 cases to study MTX therapy. In 13 patients who completed 60 months of therapy, a significant improvement was noted comparing to baseline in 9 out of 12 clinical disease variables and acute phase reactants. There was also a significant decrease in the mean daily dosage of NSAIDs. Adverse events occurred in 64% of the patients, but only 13% of the patients discontinued MTX permanently. The side effects occurred more often in older patients. RA patients treated for five years with MTX showed statistically significant clinical improvement and decrease of inflammation parameters. MTX treatment may be helpful also in patients with advanced forms of RA.
10337031 Inhibitory effects of anti-rheumatic drugs on vascular endothelial growth factor in cultur 1999 May Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis and is constitutively expressed in the synovium of rheumatoid arthritis (RA). Over-expression of VEGF may play an important role in pathogenic vascularization and synovial hyperplasia of RA. In the present study, we examined whether disease-modifying anti-rheumatic drugs (DMARDs), including bucillamine (BUC), gold sodium thiomalate (GST), methotrexate (MTX) and salazosulfapiridine (SASP), act by inhibiting the production of VEGF by cultured synovial cells of patients with RA. Treatment of cultured synoviocytes with lipopolysaccharide (LPS) significantly increased VEGF production by cultured synovial cells. BUC significantly inhibited LPS-induced VEGF production, while GST tended to inhibit the production of VEGF. The inhibitory effects on VEGF production were dose-dependent. In contrast, MTX and SASP did not affect VEGF production. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that BUC also inhibited LPS-induced VEGF mRNA expression in RA synovial cells. The present study provides the first evidence that BUC inhibits VEGF production and the expression of its mRNA in synovial cells of RA patients. Our results indicate that the anti-rheumatic effects of BUC are mediated by suppression of angiogenesis and synovial proliferation in the RA synovium through the inhibition of VEGF production by synovial cells.
10912314 DMARDs in the treatment of rheumatoid arthritis: current agents and future developments. 2000 May The purpose of this paper is to review the benefits and limitations of current disease-modifying antirheumatic drugs (DMARDs) used for the treatment of rheumatoid arthritis (RA). Literature about DMARD use in RA, both as monotherapy and in combination therapy, is reviewed. The efficacy and safety of methotrexate, antimalarials, gold-containing compounds, sulphasalazine, D-penicillamine, azathioprine and cyclosporin, as well as several new antirheumatic agents are considered. Controlled short-term clinical studies demonstrate that DMARDs are superior to placebo. Early and continuous use of DMARDs is necessary to slow joint damage and improve long-term outcomes. Unfortunately, long-term treatment with these drugs is frequently limited by loss of response and/or onset of serious adverse events. The efficacy of combination DMARD therapy has also been tested, but with mixed success, and the goals of combination DMARD therapy have yet to be fully realised. New DMARDs that have recently been introduced offer promise for future RA management.
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