Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
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| 9236525 | Epstein-Barr virus-associated lymphoproliferative disease during methotrexate therapy for | 1997 Jul | BACKGROUND: Epstein-Barr virus (EBV)-associated lymphoproliferative disorders have recently been observed during treatment of rheumatoid arthritis and dermatomyositis with low-dose methotrexate. OBSERVATION: A patient with psoriasis developed a B-cell lymphoproliferative disorder during long-term treatment with low-dose methotrexate. The lymphoid cells expressed EBV latent membrane protein 1, and the EBV viral genome was present as demonstrated by in situ hybridization. Evaluation for EBV clonality showed that the lymph node contained clonal EBV DNA. Polymerase chain reaction studies confirmed that the B-cell lymphoproliferative disorder was mainly monoclonal, suggesting that the disorder arose from a single EBV-infected B-cell clone. CONCLUSIONS: Lymphoproliferative disorders associated with Epstein-Barr virus in which the clinicopathological presentation is similar to those occurring in patients after transplantation may be observed in patients with psoriasis treated with methotrexate. While it is impossible to rule out a fortuitous occurrence of an EBV-associated lymphoproliferative disorder and psoriasis treated with methotrexate in the same patient, EBV appears to be critical in the pathogenesis of the lymphoproliferative disorder in this patient. | |
| 9227169 | Methotrexate in patients with moderate systemic lupus erythematosus (exclusion of renal an | 1997 Jun | OBJECTIVES: Methotrexate (MTX) has been used in several autoimmune diseases. Apart from its use in rheumatoid arthritis, MTX has been assessed in small studies in patients with vasculitis, uveitis, and inflammatory bowel disease. The aim of this study was to evaluate the efficacy of MTX in a particular group of patients with systemic lupus erythematosus (SLE). PATIENTS: In an open prospective study 22 patients fulfilling the ACR criteria for SLE were included. Patients had one or more of the following manifestations; active non-destructive polyarthritis, dermatitis, vasculitis of the skin, pleuritis. All patients had been treated with corticosteroids for at least six months without achieving remission. Sixteen patients were taking antimalarial drugs in addition to corticosteroids, which were stopped at the beginning of the trial. Patients with renal and central nervous involvement were excluded from the study. All patients received MTX orally at a dose of 15 mg/week over six months. Corticosteroids were continued. As additional medication only indomethacin up to 100 mg/day was permitted if used before the start of the study. The outcome was evaluated using the SLE disease activity index (SLEDAI). RESULTS: Disease activity was evaluated after six months of MTX treatment. All patients completed the study period. The SLEDAI decreased significantly from mean (SD) 12.2 (3.99) to 4 (3.75) (p = 0.001). The prednisolone dose was reduced from a mean (SD) of 17.4 (12.8) at the beginning to 8.8 (5.36) mg/day at the end point of the study (p = 0.01). MTX was well tolerated. Four patients complained of general malaise. Two patients had transient increases in liver enzymes. In no case did MTX have to be stopped. CONCLUSIONS: In an open prospective study methotrexate was used in SLE patients with particular clinical characteristics. MTX was shown to be effective in reducing disease activity and sparing the dose of corticosteroids. Further controlled studies are necessary. | |
| 10870096 | Additive effect of indomethacin and methotrexate on suppression of growth in rats. | 1999 Nov | The purpose of this study was to investigate the medium-term effects of methotrexate (MTX) and indomethacin on the growth of young rats. Four equal groups of Sprague-Dawley male rats (four animals in each group; mean+/-S.D. body weight, 183+/-13 g, in their rapid growth phase) were subjected to the following drug treatment: one group was given MTX (0.2 mg kg(-1) body weight) subcutaneously on every fourth day, another received indomethacin (2.5 mg kg(-1) body weight) subcutaneously daily and the third group was given both of these drugs (MTX on every fourth day and indomethacin daily). The fourth group was injected subcutaneously with physiological saline every day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 10 weeks. After this period, liver, spleen and kidneys were excised, weighed and analysed for MTX and dihydrofolate reductase activity. Compared with the groups, which received MTX alone, indomethacin alone, or physiological saline, mean increase (17+/-11 g) in body weight of rats was minimal in the group receiving both MTX and indomethacin. The difference was statistically significant (p=0.001) when the values of mean increase in body weight of rats in different treatment groups after a 10-week treatment were compared. The mean weights of liver and spleen in this group receiving both MTX and indomethacin were also found to be significantly less than the weights of these organs in the control group (p<0.01). There also appears to be a decline in food consumption in this group (p<0.05). This negative effect on growth of animals in this group appears to be not only due to decreased food consumption but also due to increased inhibition of de novo pathway of DNA synthesis. This is supported by increased accumulation of MTX and decreased dihydrofolate reductase activity in this group receiving both MTX and indomethacin, as compared with the group receiving MTX alone. The data indicate an additive effect of MTX and indomethacin on the suppression of growth in young rats, alluding to the notion that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving these two drugs concomitantly over a long period of time might be at a risk of experiencing short-term suppression of growth. | |
| 9210979 | Percutaneous absorption and disposition studies of methotrexate in rabbits and rats. | 1997 Jul | The absorption and disposition of methotrexate (MTX) in the plasma, synovial fluid (SF), skin, and muscle tissue were studied following administration of a topical MTX gel in rabbits and rats. In rabbits, MTX concentrations in the plasma increased steadily toward the peak (5.9 +/- 2.8 ng mL-1) which appeared at approximately 2 h postdose and declined with the elimination half-life of 4.48 +/- 1.74 h. At 1 h after the topical dose, the MTX concentrations in the skin (49.0 +/- 19.8 micrograms g-1), muscle (12.7 +/- 3.3 ng g-1), and SF (19.2 +/- 10.1 ng g-1) underneath the dosed stifle joint were significantly higher (p < 0.05) than those of the untreated stifle joint, indicating the potential therapeutic value of topical delivery of MTX for rheumatoid arthritis. A large fraction (approximately 59%) of MTX which was found in the skin at 1 h postdose was present in the stratum corneum, indicating its extensive binding capacity for MTX. The MTX concentrations in the muscle and SF of the dosed stifle joint at 1 h postdose were 1.8 and 2.6 times higher than those in the dosed elbow joint, respectively, reflecting the effect of dose site on the permeation of MTX. Using a new filter paper method, the amounts of SF obtained from the elbow and stifle joints of four rabbits were 26.3 +/- 8.3 and 48.8 +/- 5.2 mg, respectively. A significant enhancer effect of N,N-diethyl-n-toluamide (DEET) on the disposition of MTX in the stratum corneum of rabbit ear was observed (p < 0.05) by the tape-stripping method. In rats, the gel containing 4% DEET resulted in a twofold increase in the permeation of MTX into the muscle over the 4 h period postdose. A modified HPLC method with a linear calibration curve (r > 0.999) over the range of 2-50 ng mL-1. quantitation limit of 0.5 ng mL-1, and mean recovery of approximately 87% was used for the quantitation of MTX in the tissue and fluid samples. | |
| 11745919 | Folinic acid protects against suppression of growth by methotrexate in mice. | 2001 May | The objective of this study was to investigate whether folinic acid supplementation would protect young mice against suppression of growth by methotrexate (MTX). Four equal groups of Balb/c young male mice (5 animals in each group; mean+/-SD body weight 9.64+/-0.85 g, in their rapid growth phase) were subjected to the following drug treatment: One group was given MTX (3.5 mg/kg body weight) intraperitoneally on every 2nd day, another received folinic acid (7.0 mg/kg body weight) intraperitoneally every 2nd day. The third group was given both of these drugs (MTX on every 2nd day and folinic acid 8 h post-MTX injection). The fourth group was injected with physiological saline every other day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 3 weeks. After this period mice were sacrificed and liver, spleen and kidneys were excised, weighed and analyzed for MTX and dihydrofolate reductase activity. A small segment of the proximal part of small intestine and small pieces of liver and kidney were also removed to study morphological changes. Compared to the groups, which received folinic acid alone, folinic acid plus MTX or physiological saline, mean increase in body weight (6.8+/-0.8 g) of mice over a period of 3 weeks was minimal in the group receiving MTX alone (one-way ANOVA p=0.0001). The mean weights of liver and kidney in this group receiving MTX alone were also found to be significantly less than the mean weights of these organs in the 3 groups (p<0.001). The negative effect on growth of animals appears not only due to malabsorption but inhibition of pathway of de novo DNA synthesis may also be involved. This is supported by loss of villous pattern in small intestine of mice treated with MTX alone and increased accumulation of free MTX and decreased dihydrofolate reductase in the liver of the group receiving MTX alone as compared with the group receiving MTX plus folinic acid. The data indicate that the administration of folinic acid protects mice against suppression of growth by MTX. On the basis of these observations it can be deduced that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving MTX over a long period of time might be at a risk of experiencing short-term suppression of growth, however they could benefit from supplementation with folinic acid. | |
| 15253402 | Management of rheumatoid arthritis. | 2004 May | The past few years have witnessed a major change in the approach to the treatment of rheumatoid arthritis. The present focus is on early recognition and prompt treatment with disease-modifying antirheumatic drugs of which methotrexate continues to be the drug of choice. Leflunomide is an important recent addition to the list of available drugs. The use of combinations of disease-modifying antirheumatic drugs is gaining wide acceptance. A better understanding of the pathobiology of rheumatoid arthritis has led to the development of targeted therapies such as tumour necrosis factor blockers. There are robust data to show the clinical utility of tumour necrosis factor blockers in patients with rheumatoid arthritis. | |
| 14531955 | Atherosclerotic cardiovascular disease in rheumatoid arthritis. | 2003 Aug | The past 3 years have seen a remarkable growth in the interest of cardiovascular disease in rheumatoid arthritis. There have been studies published documenting an increased incidence and prevalence of cardiovascular conditions in patients with rheumatoid arthritis compared with individuals without rheumatoid arthritis. There has also been interest in the occurrence of cardiovascular risk factors in rheumatoid arthritis and in the role of antirheumatic therapy, including cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs, methotrexate, corticosteroids, and tumor necrosis factor inhibitors. A number of studies using noninvasive means to detect atherosclerosis have shown that patients with rheumatoid arthritis may be prone to atherosclerosis. This information should be important to physicians who provide care to patients with rheumatoid arthritis, given the difficulty of recognizing cardiovascular signs and symptoms among patients with the disease. | |
| 14731052 | Infliximab: a pharmacoeconomic review of its use in rheumatoid arthritis. | 2004 | Infliximab (Remicade), a biological disease-modifying antirheumatic drug (DMARD), binds to and inhibits the activity of tumour necrosis factor-alpha, which is thought to play an important role in the pathophysiology of rheumatoid arthritis. Intravenous infliximab plus methotrexate is recommended in patients with rheumatoid arthritis who have not achieved satisfactory disease control with adequate courses of other DMARDs. Pharmacoeconomic analyses have been based on efficacy data from the pivotal placebo-controlled Anti-Tumour Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial in patients with active, refractory rheumatoid arthritis. Infliximab every 8 weeks plus methotrexate demonstrated rapid and sustainable improvements in clinical response, delayed radiographic progression, and/or improved functional status and health-related QOL compared with placebo plus methotrexate at weeks 30, 54 and 102. In cost-utility analyses of infliximab plus methotrexate conducted from a healthcare payer and/or societal perspective in the US, Europe, Portugal, Sweden and the UK, infliximab 3 mg/kg every 8 weeks plus methotrexate was associated with acceptable (<$US50,000 per discounted QALY gained) cost-utility ratios relative to methotrexate alone in patients with active, refractory rheumatoid arthritis. When only direct costs were considered, the lifetime incremental cost per discounted QALY gained with infliximab plus methotrexate relative to methotrexate alone was $US30,500-38,700 (year of costing 1998 or not reported; treatment duration 54 or 102 weeks or lifelong) in the US and Europe analyses, and euro39 500 (year of costing not reported; lifelong treatment) in the Portuguese analysis. The cost-utility ratios were more favourable when lost productivity costs or the additional benefit of infliximab on radiographic stabilisation were considered. In the Swedish and UK analyses with a 10-year time horizon, infliximab plus methotrexate for 1 or 2 years was associated with cost-utility ratios of euro28 600-56 100 (year of costing not reported) when direct costs were considered, and euro3440-48 200 when direct costs plus loss-of-productivity costs were considered. In conclusion, cost-utility analyses, which were based on modelling of data from the pivotal clinical trial of infliximab plus methotrexate, indicate that infliximab plus methotrexate is associated with acceptable cost-effectiveness ratios (<$US50,000 per discounted QALY gained) relative to methotrexate monotherapy in patients with active rheumatoid arthritis who have not responded to previous methotrexate or other DMARD therapy. The cost effectiveness of infliximab versus other DMARDs is at present unclear, but will be clarified when appropriate data from directly comparative clinical and/or pharmacoeconomic studies become available. In patients in whom adequate courses of other DMARDs have failed to achieve satisfactory disease control, infliximab plus methotrexate may prevent or delay disability, which may produce reductions in nondrug costs that can help offset its acquisition cost. | |
| 15301984 | The treatment of rheumatoid arthritis. | 2004 Aug | The treatment of rheumatoid arthritis has changed dramatically in the last 10 years and in parallel the definition and expectations of patients and clinicians of the effects of disease-modifying anti-rheumatic agents has changed as well. Current expectations of efficacy now include improvement of signs and symptoms of disease activity as well as slowing, if not complete inhibition, of disease progression as measured by X-ray progression along with significant improvement in patient physical function. In addition, clinicians assess the safety profile of these agents more critically in an attempt to improve the risk:benefit profile. Drugs, such as methotrexate, sulfasalazine and leflunomide have provided patients with substantial relief of symptoms and improvement in terms of X-ray progression, but they have been hampered by the occurrence of significant adverse events along with the inability to maintain benefit for prolonged periods of time. With the increased understanding of the basic biological mechanisms of the disease process, there has been the introduction of four biological disease modifying therapies and other drugs into clinical practice, which have altered aspects of the risk:benefit ratio for patients with various rheumatic diseases. | |
| 15623977 | Biological agents in rheumatoid arthritis. | 2004 Oct | Rheumatoid arthritis (RA) is the commonest inflammatory joint disease with considerable morbidity and mortality. Conventional disease-modifying antirheumatic drugs like methotrexate form the cornerstone of therapy. However, they have several limitations in terms of slow onset of action, adverse effects and modest remission and retention rates. Several cytokines are involved in the pathogenesis of RA. Biological agents that specifically inhibit the effects of tumour necrosis factor-a (TNF-a) or Interleukin-1 (IL-1) represent a major advancement in the treatment of RA. By targeting molecules that are directly involved in the pathogenesis of RA, these therapies are proving to be efficacious, highly specific and better tolerated than standard therapies. The use of these agents needs to be monitored carefully for possible side-effects, including the development of infections. Additional anti-cytokine agents for the treatment of RA are under further development. | |
| 12491122 | [Pharmacotherapy of rheumatoid arthritis]. | 2002 | The therapeutic goals in rheumatoid arthritis have been so far pain reduction, improvement of function and inhibition of disease progression. Nowadays therapeutic strategies must aim at the induction of remission. Long-term results clearly improve with an early start of DMARD therapy. Additional corticosteroid therapy can further reduce joint destruction. After an early start with DMARD therapy (methotrexate in most cases) corticosteroids should be additionally given in moderate and severe cases. Reconsideration of the therapeutic regime should be performed no later than three months after start of therapy. In the case of remission corticosteroids should be reduced. If there is no remission the DMARD therapy should be intensified, if necessary together with a combination therapy. After another three months a step-down concept can be applied if remission occurs. Otherwise therapy should again be intensified, if necessesary with the use of biologicals. | |
| 12848982 | Sex hormones and rheumatoid arthritis. | 2002 Oct | Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone as natural immune-suppressors. In male rheumatoid arthritis (RA) patients, androgen replacement seems to ameliorate the disease and supports their involvement in the pathophysiology of the disease. The combination of androgens with cyclosporin A or methotrexate has been found to potentiate the apoptosis of monocytic inflammatory cells as well as to reduce the cell growth at least in vitro. Considerable interest has been devoted in the last years as to whether the use of oral contraceptive pills (OCs) may have a protective effect on the risk of RA. The results of many controlled studies have been found contradictory. At the present time, no consensus has been achieved regarding OCs administration and its relationship to the prevention or development of RA. In addition, an association of estrogen receptor gene polymorphism with age at onset of RA has been observed and might further explain inter-individual clinical and therapeutical-response variations. Local increased estrogen concentrations and decreased androgen levels have been observed in RA synovial fluids and seem to play a more important role in the immune/inflammatory local response. | |
| 11934345 | Pharmacoeconomics of long-term treatment of rheumatoid arthritis. | 2002 Apr | Rheumatoid arthritis affects ~ 1% of the population. It is associated with pain, deformity, decreased quality of life and disability that in turn affects patients' ability to work. A variety of disease-modifying antirheumatic drugs are available to control the disease activity of rheumatoid arthritis. The goal of treatment is to improve patients' quality of life and prevent joint destruction. This paper reviews both the clinical aspects of frequently prescribed disease-modifying antirheumatic drugs and the available cost-effectiveness information. Clinical evidence supports the effectiveness of methotrexate, etanercept, infliximab, gold, hydroxychloroquine, leflunomide, sulfasalazine, penicillamine, cyclosporin, azathioprine and corticosteroids. The last four of these are associated with greater toxicity and are only used if less toxic drugs are ineffective. The lack of published economic evaluations of disease-modifying antirheumatic drugs highlights the need for such studies to allow efficacious and cost-effective drugs to be used to prevent the long-term complications of uncontrolled rheumatoid arthritis. | |
| 12959625 | Quality of life in patients with rheumatoid arthritis : which drugs might make a differenc | 2003 | Rheumatoid arthritis (RA) is a chronic, disabling, inflammatory polyarthritis that affects patient well-being and QOL. Many disease-modifying antirheumatic drugs (DMARDs) are available for treating RA but patients are often refractory to treatment. The goal of treatment is to improve both general health and health-related QOL. Generic and disease-specific instruments exist to measure QOL. Using these instruments, one can determine if QOL improves with treatment. If the minimal clinically important difference (MCID) for the instrument is known, one can determine if the change is clinically significant. The literature was reviewed in a systematic manner to determine which drugs could affect QOL in patients with refractory RA. Refractory RA is poorly defined but we used the definition of failing at least two DMARDs. Methotrexate, leflunomide, cyclosporin, glucocorticoids, etanercept and infliximab clinically and statistically significantly improved QOL in patients with RA. Gold and epoetin-alpha (erythropoietin) statistically improved QOL in patients with RA but the clinical significance of the improvements could not be determined. These studies were either in non-refractory populations or the refractoriness could not be determined. Further study is required to determine the response of QOL to treatment in patients with refractory RA and instruments with known MCIDs should be used so that the clinical significance of the improvement can be determined. | |
| 15157001 | Pursuit of optimal outcomes in rheumatoid arthritis. | 2004 | The aim of this review is to describe methods of quantifying disease activity and symptomatology and discuss treatment goals for rheumatoid arthritis (RA). The benefits and limitations of existing therapeutic approaches, the importance of early therapy in preventing disease progression and the place of biologicals in early therapy will be discussed. Disease activity and symptomatology in RA are often measured using a set of core endpoints that incorporate pain, patient global assessment, physical disability, swollen joints, tender joints, acute phase reactants, physician global assessment and radiographic imaging of joints. Imaging of joints is the only means by which to measure the effects of disease-modifying antirheumatic drugs (DMARDs) on the irreversible joint damage that occurs during RA. There is increasing evidence that this damage and its functional consequences occur early in the onset of disease. The consensus is that patients with RA should be treated with DMARDs earlier rather than later in the disease process. Remission, or a state of sustained response or low disease activity that is not damaging or disabling, is the ideal goal of therapy for RA, but formal criteria defining a state of remission need to be revised and, ideally, updated to include a radiographic component. Currently available DMARDs are limited in their ability to achieve early, sustained response or remission, by delayed onset of action, cumulative toxicity and lack of long-term therapeutic response. It is hoped that the emergence of novel DMARDs--targeted biological agents, such as anti-tumour necrosis factor-alpha (anti-TNF-alpha)--will help to counteract such limitations and will allow early DMARD use to be adopted as standard practice in place of their use as a last resort therapy after failure of other treatment. One such biological agent, etanercept, has been shown to reduce radiographic disease progression and induce overall clinical response during the early stages of RA. It is significantly more effective and fast-acting than methotrexate, one of the most effective, commonly used DMARDs. | |
| 12468813 | Evidence from clinical trials and long-term observational studies that disease-modifying a | 2002 Dec | Earlier reports, including a comprehensive 1983 review, had indicated that slowing of radiographic progression was relatively unusual in treatment of rheumatoid arthritis (RA) using traditional disease modifying anti-rheumatic drugs. However, in recent years, slowing of radiographic progression has been documented in a number of clinical trials, as well as long-term observational studies, with use of (in alphabetical order) adalimumab, anakinra, corticosteroids, cyclophosphamide, cyclosporin, etanercept, gold salts, infliximab, leflunomide, methotrexate and sulphasalazine. At this time, disease modification is a realistic goal in the clinical care of patients with RA. Documentation of improved long-term outcomes requires long-term observational data over 5-20 yr to supplement data from randomized controlled clinical trials over 6-24 months. | |
| 15130461 | The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis | 2004 May | OBJECTIVES: To review the evidence of the clinical and cost-effectiveness of anakinra, an interleukin-1 receptor antagonist (IL-1Ra), for the treatment of rheumatoid arthritis (RA) in adults. DATA SOURCES: Electronic bibliographic databases. Scrip, Food and Drug Administration (FDA) submissions for new drug applications, European Agency for the Evaluation of Medicinal Products (EMEA) reports and the pharmaceutical company submission to the National Institute for Clinical Excellence. REVIEW METHODS: Studies were identified that included randomised controlled trials (RCTs) or economic evaluations of anakinra in adult patients with RA. Existing health economic reviews were also assessed. Data were extracted and quality assessed using a structured approach. The Birmingham Rheumatoid Arthritis Model (BRAM) was used to compare disease-modifying antirheumatic drug (DMARD) sequences, chosen to reflect current clinical practice, with and without anakinra, at different points in the DMARD sequence. RESULTS: Five high-quality RCTs of anakinra in adult patients with RA, involving a total of 2905 patients, of whom 2146 received anakinra, were identified. The results of the clinical trials were consistent with clinical benefit (compared with placebo) as measured by American College of Rheumatology (ACR) composite response rate at 6 months. Variation in response rate was seen across the trials, which is likely to be a reflection of the size of the trials and the wide range of doses evaluated. Consistent benefit was seen at the higher dose evaluated. Benefit was evident both with monotherapy and when used in combination with methotrexate. Data on the efficacy end-points evaluated in a large pragmatic safety study have not been made available, which is of concern. Anakinra treatment was associated with a high incidence of injection-site reactions. Serious adverse events were infrequent, but longer term follow-up is required. No fully published economic evaluations of anakinra in patients with RA were identified. The BRAM gives a base-case estimate of the incremental cost-effectiveness ratio (ICER) of anakinra of 106,000 pounds to 604,000 pounds/quality-adjusted life-year (QALY). In the sensitivity analyses substantial variations were made in key parameters and ICERs were shown to be responsive. However, ICERs did not drop below 50,000 pounds/QALY in any univariate sensitivity analysis. CONCLUSIONS: Anakinra can be considered modestly effective in the treatment of RA based on ACR response, although no conclusion can currently be made on the effect of treatment on disease progression. Adjusted indirect comparison suggests that anakinra may be significantly less effective at relieving the clinical signs and symptoms of RA, as measured by the ACR response criteria, than tumour necrosis factor (TNF) inhibitors all used in combination with methotrexate, although these results should be interpreted with caution. The BRAM produces an ICER for anakinra substantially higher than those for infliximab and etanercept. However, patients may respond to anakinra when they have not responded to other TNF inhibitors, as these agents have a different mechanism of action. Thus, anakinra may produce a clinically significant and important improvement in some patients that they could not otherwise have achieved. Further research would be valuable in the following areas: RCTs to evaluate the efficacy, safety and cost of anakinra over the longer term; comparative trials of anakinra with other DMARDs and biological modifiers; assessment of the role of anakinra in the treatment of patients who have failed to achieve a benefit while taking infliximab or etanercept; assessment on the impact of DMARDs and anakinra on joint replacement, mortality and quality of life; controlled clinical trials of combination therapy with two anticytokines; investigations into newer biological therapies; and the utility of radiographic outcomes in clinical trials of RA. | |
| 12491120 | [Current aspects of cost effectiveness of TNF-alpha blocking agents in patients with rheum | 2002 | Facing increasing health-related costs and limited health care resources, the assessment of cost effectiveness (CE) of medical procedures is also gaining considerable importance in the field of rheumatology. Since high annual therapy costs of 17,000-21,000 Euro are related to the employment of TNF-alpha blocking agents such as etanercept and infliximab (compared to annual costs of 350-5000 Euro of other disease modifying drugs (DMARDs) in the treatment of rheumatoid arthritis (RA)), their CE has become an important issue. The present investigation summarizes economic evaluations of cost and effectiveness of TNF-alpha blocking agents and compares the results to those of traditional DMARD therapies in patients with RA. The implications of these economic results on the further use of TNF-alpha blocking drugs and methodological improvements of their economic evaluation are discussed. The current literature provides evidence for the CE of the combination therapy with methotrexate (MTX), hydroxychloroquine (HCQ), and sulfasalazine (SASP). In comparison to this finding, the use of etanercept and MTX yields much higher costs, although the highest rate of ACR20 responses is achieved by this combination (additional costs of $42,000 per ACR20 response compared to combination of MTX, HCQ, and SASP). Two recent studies show more promising results of about $12,000/QUALY and even cost savings per QUALY administering etanercept and infliximab, respectively. The wide range of the CE ratios is mainly explained by different methodological approaches. Whether the wider employment of TNF-alpha blocking drugs (comprising not only selected patients) proves to be economically effective, remains to be investigated by further economic analyses. In contrast to the initial disappointing results of the comparison of established DMARD therapies and TNF-alpha blocking drugs in terms of CE, recently published data renders evidence that the CE of the TNF-alpha blocking drugs is comparable to other accepted therapies in internal medicine. | |
| 14989426 | Effects of DMARDs on IL-1Ra levels in rheumatoid arthritis: is there any evidence? | 2002 Sep | Recent research has shown that in the processes of rheumatoid arthritis (RA), interleukin-1 (IL-1) is one of the pivotal cytokines in initiating and driving the disease, and the body's natural response, IL-1 receptor antagonist (IL-1Ra), has been shown conclusively to block its effects. Several agents used to treat RA such as disease modifying antirheumatic drugs (DMARDs), as well as glucocorticoids (GC), affect the transcription, synthesis, release, and/or activity of cytokines, including the IL-1Ra. A higher ratio of IL-1Ra:IL-1 production by the peripheral blood mononuclear cells (PBMC) of RA patients successfully treated with methotrexate (MTX) is observed when compared with the PBMC of untreated patients or healthy controls. Recent studies have also shown a significant increase in IL-1Ra with low-dose MTX treatment of cultured monocytic cells. Antimalarials (hydroxychloroquine and chloroquine) have been found to increase the monocyte production of IL-1Ra and these changes might explain at least some of their mechanisms of action. Various studies have shown that leflunomide (LF) tends to favor the inhibition of pro-inflammatory and matrix-destructive factors over that of anti-inflammatory factors (i.e. IL-1Ra) and metalloproteinase inhibitors, thus interfering with both inflammation and tissue destruction. Further studies should investigate the effects of LF on synovial tissue/fluid expression of the IL-1Ra in treated RA patients. Regarding cyclosporin A (CyA), considerable evidence shows that the treatment of RA patients induces a decrease in IL-1Ra levels. Similar results with the inhibition of IL-1Ra mRNA and protein have been observed following RA treatment with glucocorticoids. In addition, the oral administration of cortisol to normal subjects also decreased LPS-induced IL-1Ra synthesis in cultured monocytes. The effects of different DMARDs and GC on IL-1Ra levels in RA patients, as reviewed in this paper, support the important role that selected anticytokine treatments might exert in the pathophysiology of the disease. | |
| 12916876 | A case of clinical indolent natural killer cell lineage large granular lymphocytic leukemi | 2003 Jul | We report a case of natural killer (NK) cell leukemia with unusual biological features in a 65-year-old woman with a 20-year history of rheumatoid arthritis. She presented with neutropenia, thrombocytopenia, splenomegaly and bone marrow infiltration. Immunophenotyping (CD2+ CD3- CD4- CD5- CD8- CD16+ CD56-) confirmed NK cell leukemia. Her neutropenia and thrombocytopenia resolved following splenectomy and she has remained well with stable disease for 12 months on oral low-dose methotrexate. In contrast to all previous reports, in this instance the phenotype of large granular lymphocytic (LGL) leukemia occurring in the context of rheumatoid arthritis was NK-cell rather than T-cell. Furthermore, the clinical course was indolent, whereas, all prior literature reports have described a very aggressive clinical course for this disorder with a median survival of just 3.5 months. This case illustrates previously unrecognized heterogeneity in the natural history of this disorder. |