Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 15172042 | Leflunomide. | 2004 May | Leflunomide is a low-molecular weight, synthetic, oral agent specifically developed for immunosuppression. Because of activity in animal models, leflunomide was tested in rheumatoid arthritis(RA). These investigations have demonstrated that leflunomide reduces the clinical symptoms and signs of RA, improves health related quality of life, and retards structural damage. Leflunomide has been evaluated in RA patients as monotherapy and in combination with methotrexate. Close monitoring for adverse events with particular attention for monitoring liver enzymes for hepatic toxicity is important during treatment with leflunomide. | |
| 12064828 | A cost effectiveness analysis of treatment options for methotrexate-naive rheumatoid arthr | 2002 Jun | OBJECTIVE: New treatment options for patients with methotrexate (MTX)-naive rheumatoid arthritis (RA) have become available. Given wide variability in efficacy and cost among different treatment options, we sought to determine their relative cost effectiveness to help guide policy in different cost constrained settings. METHODS: We performed a cost effectiveness analysis comparing 5 monotherapy options for patients with MTX-naive RA: (1) etanercept, (2) leflunomide, (3) MTX (up to 15 mg weekly), (4) sulfasalazine (SSZ), and (5) no second line agent. A decision analysis model was used with a time horizon of 6 months. We employed 2 measures of effectiveness based on published clinical trial data: American College of Rheumatology (ACR) 20% response proportion (ACR 20) and a weighted average of proportions achieving ACR 70, ACR 50, and ACR 20 (ACR 70 weighted response, ACR 70WR). Incremental cost effectiveness ratios were calculated as additional cost per patient achieving either outcome, compared with the next most expensive option. RESULTS: In both base case analyses employing ACR 20 and ACR 70WR as effectiveness measures, MTX and SSZ both cost less and were more effective (i.e., cost saving) than no second line agent. Leflunomide cost more and was less efficacious than SSZ (dominated) in analyses using either outcome. The most efficacious option, etanercept, cost US $41,900 per ACR 20 and $40,800 per ACR 70 WR compared with SSZ and MTX, respectively. When we included only direct costs in analyses, the least expensive non-dominated option was SSZ with incremental cost effectiveness ratios of US $900 per ACR 20 and $1500 per ACR 70WR compared with no second line agent. Overall, relative cost effectiveness between MTX and SSZ was sensitive to variation in relevant variables in sensitivity analyses. Otherwise, our extensive sensitivity analyses did not substantially affect the base case results. CONCLUSION: MTX is cost effective (cost saving vs the no second line agent option) for MTX-naive RA in achieving ACR 20 or ACR 70WR over a 6 month period. Based on available data, the relative cost effectiveness between SSZ and MTX cannot be determined with reasonable certainty and SSZ therapy appears to be as cost effective as MTX (cost saving) in achieving ACR outcomes over a 6 month period. The most efficacious option, etanercept, incurs much higher incremental costs per ACR 20 or ACR 70WR than other options analyzed. Whether etanercept compared with MTX is cost effective depends on whether > $40,000 per ACR 20 or ACR 70WR over a 6 month period is considered acceptable. | |
| 12379516 | Potential therapeutic uses of interleukin 1 receptor antagonists in human diseases. | 2002 Nov | OBJECTIVE: To review publications relating to the blocking of interleukin 1 (IL1) as a strategy for treating human disease, ranging from rheumatoid arthritis (RA) to Alzheimer's disease. METHODS: The National Library of Medicine's PubMed database was searched for articles about pharmaceutical agents that reduce the biological actions of IL1. RESULTS: Fish oils and corticosteroids were identified as non-selective pharmacological interventions that reduce the activity of IL1, whereas a recombinant human IL1 receptor antagonist (anakinra) and a soluble recombinant type I IL1 receptor act selectively. To date, anakinra is the only selective intervention that has been shown in controlled clinical trials to be effective and well tolerated in the treatment of a specific human disorder, RA. In controlled clinical trials, anakinra provided significant clinical improvement and slowed radiographic disease progression in patients with active RA. Moreover, addition of anakinra to existing methotrexate treatment significantly reduced signs and symptoms of active disease. CONCLUSIONS: The clinical use of anakinra has been demonstrated in the management of RA, but blocking of IL1 in other human disorders, as well as the safety of the use of these blocking agents in chronic diseases, still needs to be defined by controlled clinical investigations. | |
| 15334454 | Regional variation and differential response to therapy for knee synovitis adjacent to the | 2004 Aug | OBJECTIVE: To use magnetic resonance imaging (MRI) to investigate the importance of knee joint synovitis at the cartilage-pannus junction (CPJ) in rheumatoid arthritis (RA) as compared with synovitis at a distant site in the suprapatellar pouch (SPP) and as compared with CPJ synovitis in the spondylarthropathies (SpA), and to assess the relative response of knee joint synovitis to therapy at the CPJ and SPP sites. METHODS: Dynamic contrast-enhanced MRI (DEMRI) of actively involved knee joints in 24 patients (13 with RA and 11 with SpA) was undertaken. The area of synovitis was calculated at the CPJ and SPP regions of interest in patients with RA and in patients with SpA. Differences in CPJ and SPP synovitis were determined using calculated DEMRI parameters which included the initial rate of contrast enhancement (IRE) and the maximal enhancement (ME). Changes in the synovial area at the CPJ and SPP were also measured in 10 patients with early RA, following treatment with disease-modifying antirheumatic drugs (DMARDs) (either methotrexate or leflunomide). RESULTS: In patients with RA or SpA, the area of synovitis was significantly larger immediately adjacent to the CPJ compared with a distant site at the SPP (in RA, mean synovitis area 162 mm2 at the CPJ versus 114 mm2 at the SPP [P = 0.010]; in SpA, mean synovitis area 214 mm2 at the CPJ versus 143 mm2 at the SPP [P = 0.002]), but the differences in the areas of synovitis at these sites were not significant between the RA and SpA patients. The IRE and ME values were also higher at the CPJ compared with the SPP, both in the RA patients (IRE P = 0.054, ME P = 0.018) and in the SpA patients (IRE P = 0.002, ME P = 0.001). A larger reduction in the area of synovitis was seen at the SPP compared with the CPJ following DMARD therapy in the RA patients (mean reduction 35% at the SPP [P = 0.023] and 12% at the CPJ [P not significant]). CONCLUSION: The non-disease-specific variations in synovitis and the differential responses to therapy in RA patients have implications for improving our understanding of CPJ synovitis. The results suggest that the pathophysiologic events at the CPJ reflect common anatomic, immune system, or biomechanical factors that play a role in modulating the severity of arthritis, and these events are not specific to RA since the same process was observed in other arthritides. | |
| 15794194 | Which factors are related to the presence of atherosclerosis in rheumatoid arthritis? | 2004 | OBJECTIVE: An accelerated progression of atherosclerosis may contribute to the increased mortality due to cardiovascular disease reported in rheumatoid arthritis (RA). The aim of this study was to identify variables, related to disease onset as well as to disease progression, of importance for the presence of atherosclerosis, as diagnosed by B-mode ultrasonography, in patients with medium-term RA. The results are based on the co-analysis of retrospective data as well as cross-sectional data. The impact of RA per se on atherosclerosis was evaluated relative to age- and sex-matched controls. METHODS: Thirty-nine RA patients, with a maximum age of 65 years, who had previously been included in a large retrospective cohort study, were assessed by duplex scanning after a disease duration of 19-23 years. In the present study, factors identified in the two earlier studies were assessed for their potential relationship with intima-media wall thickness (IMT) of the common carotid artery (CCA), and the presence and grade of atherosclerotic plaques of the CCA and the common femoral artery, in regression models. The candidate co-variates were: variables reflecting inflammatory activity at disease onset and at the time of ultrasound assessment, established cardiovascular risk factors, pharmacological treatment [corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs)], and the presence of complications and co-morbidity identified during disease progression, as well as lipid levels, anti-lipid antibodies, haemostatic factors, and markers of immune activation measured at ultrasound assessment. RESULTS: In patients with RA, analysis of simple linear regression models revealed those variables significantly associated with IMT-CCA to be age, tissue plasminogen activator (tPA) antigen, cholesterol, low density lipoprotein (LDL)-cholesterol, triglycerides, and atherosclerotic plaques while neither inflammatory status at disease onset, traditional cardiovascular risk factors, or pharmacological treatment during disease had any significant impact on IMT. In an estimated multiple linear regression model, variables associated with increasing log of IMT-CCA were the log of cholesterol and of soluble intracellular adhesion molecule 1 (sICAM-1), while methotrexate treatment tended to have a decreasing effect. In simple binary logistic regression, atherosclerotic plaques were associated with age, IMT-CCA, smoking, and the levels of sICAM-1, sE-selectin, interleukin-2 soluble receptor alpha (IL-2sRalpha), plasminogen activator inhibitor-1 (PAI-1) mass, cholesterol, LDL-cholesterol, and the LDL/high density lipoprotein (HDL) ratio. A multiple approach indicated that plaques were associated with age, cholesterol, and sE-selectin. Severe plaques were associated with LDL-cholesterol and disease duration. Logistic regression in the age- and sex-matched case-control study revealed that IMT-CCA was, together with the D-dimer, associated with RA per se. CONCLUSION: Levels of lipids and adhesion molecules were associated with the presence of atherosclerosis in RA. IMT-CCA was associated with RA per se. Disease duration could predict severe atherosclerotic plaques. Treatment with methotrexate seemed to decrease the IMT-CCA. | |
| 12022903 | Leflunomide-associated skin ulceration. | 2002 Jun | OBJECTIVE: To report a case of skin ulceration as a result of treatment with leflunomide for rheumatoid arthritis. CASE SUMMARY: A 78-year-old white woman developed bilateral leg ulcers after 6 months of treatment with leflunomide for rheumatoid arthritis. A history of leg ulcers after methotrexate therapy had been documented. Serologic and diagnostic tests did not support an alternate process. Other medications prescribed were oral ethinyl estradiol 0.05 mg/d, felodipine 5 mg/d, and paroxetine 20 mg/d, for which no documented correlation with the skin breakdown could be made. DISCUSSION: This is the first published case describing a possible relationship between the use of the immunosuppressant agent leflunomide and skin ulceration. CONCLUSIONS: Skin breakdown and ulceration is a recognized adverse effect of drugs with immunosuppressant activity such as methotrexate. Leflunomide, a newer agent prescribed in the treatment of rheumatoid arthritis, may now be listed among the drugs in this category associated with this adverse drug effect. | |
| 12510366 | [Adalimumab]. | 2002 Dec | Recently, the anti-tumor necrosis factor(TNF)-alpha treatments for RA are successful in alleviating the discomforts associated with swollen, painful joints. Adalimumab(D2E7) is the first fully human anti-TNF-alpha monoclonal antibody(IgG1). Therefore, it has low immunogenicity and possibly greater therapeutic potential compared with other anti-TNF-alpha antibodies. This is administered subcutaneously at a dose of 1 mg/kg biweekly. The combined therapy with methotrexate(MTX) is efficacious to the patients who receive MTX alone and are insufficient to control symptoms of RA. The therapeutic effects become evident within 24 hours to one week after administration and reached maximum effect after one to two weeks. In adalimumab recipient, radiographic progression is also controlled and serum levels of matrix metalloproteinase-1(MMP-1) and MMP-3 decrease. For patients with RA, the treatment of adalimumab will set a new standard for symptom control and joint protection. | |
| 12860733 | Long term structural effects of combination therapy in patients with early rheumatoid arth | 2003 Aug | OBJECTIVE: To evaluate whether early combined therapy with methotrexate (MTX) and sulfasalazine (SSZ) during the first year in early rheumatoid arthritis (RA) induces long term beneficial effects, compared with monotherapy, when the further treatment strategy is a free choice. STUDY DESIGN: five year multicentre prospective longitudinal trial. PARTICIPANTS: 146/205 patients with RA previously included in a one year prospective randomised trial comparing the effects of treatment with MTX, SSZ, or a combination of both. Criteria for inclusion: patients with early RA (< or =1 year duration). Follow up: between the end of years 1 and 5, patients were followed up and treated by their own rheumatologist, who was allowed to indicate any treatment. OUTCOME MEASURES: disease activity score (DAS), health assessment questionnaire (HAQ), and Sharp/van der Heijde radiological score at baseline and after five years of follow up. ANALYSIS: comparison of the five year follow up DAS, HAQ, and radiological scores in patients given combined and single treatment during the first year. RESULTS: At the end of the five years of follow up, the patients primarily receiving single or combined treatment had similar mean DAS, HAQ, and radiographic scores. CONCLUSION: Treatment of patients with early RA using combined therapy with MTX and SSZ during the first year did not influence the long term inflammatory status, or disability, or structural changes, compared with single disease modifying antirheumatic drug treatment. | |
| 15322813 | Pulmonary abscess due to leflunomide use in rheumatoid arthritis: a case report. | 2005 Mar | A 43-year-old woman had rheumatoid arthritis (RA) for 5 years and complained of fever, arthralgia/myalgia, and night sweating for a month. She had been receiving only leflunomide (20 mg/day) for 5 months. On admission, there was no evidence of active arthritis or vasculitic lesion. Laboratory evaluation showed an erythrocyte sedimentation rate of 145 mm/h and C-reactive protein of 160 mg/dl. All cultures were negative. Chest radiograph and computed tomography (CT) revealed a pulmonary abscess. Staphylococcus aureus multiplied in the culture of a purulent sample obtained from the abscess under ultrasonography. The leflunomide was stopped, and sultamicillin (IV 4x2 g/day) was started for a further 6 weeks. Four weeks later, the patient had completely recovered and CT showed significant improvement of the pulmonary abscess. Ten milligrams/day of prednisolone and 7.5 mg/week of methotrexate were started for RA treatment. The patient has been under control for 5 months without any further abscess or RA activation. | |
| 15088287 | Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration | 2004 Apr | OBJECTIVE: To determine the bioavailability of higher oral doses of methotrexate (MTX) in adult patients with rheumatoid arthritis (RA). METHODS: A pharmacokinetic analysis was performed in 15 patients with RA taking a stable dose of MTX (> or = 25 mg weekly). Separated by 2 weeks, a pharmacokinetic analysis was performed in each patient after oral and subcutaneous administration of the same dose of MTX. MTX serum concentrations were measured by a fluorescence polarization immunoassay. Pharmacokinetic analysis was performed with an iterative 2-stage Bayesian population procedure, obtaining population and individual pharmacokinetic parameters. RESULTS: The median MTX dose was 30 mg weekly (range 25-40 mg). A 2-compartment model best described the serum MTX concentration versus time curves. The mean bioavailability after oral MTX was 0.64 (range 0.21-0.96) compared to subcutaneous administration. There was a statistically significant difference in the bioavailability of the 2 administration regimens. CONCLUSION: Bioavailability of a higher oral dose of MTX in adult patients with RA is highly variable, and on average two-thirds that of the subcutaneous administration. To improve efficacy of MTX at dosages of 25 mg weekly or more, a change to parenteral administration should be considered. | |
| 15361375 | Influence of guideline adherence on outcome in a randomised controlled trial on the effica | 2004 Oct | OBJECTIVE: To study the influence of rheumatologists' adherence to a methotrexate guideline on efficacy and toxicity in the treatment of rheumatoid arthritis. METHODS: In a 48 week randomised controlled trial of methotrexate, comparing folates with placebo, rheumatologists were advised on methotrexate dosage using a guideline reflecting daily practice. The influence of guideline non-adherence on outcome was analysed using generalised estimating equations and survival analysis. RESULTS: In 51% of the 411 study patients the guidelines were always followed. Non-adherence resulted in lower doses of methotrexate in 25% of cases, and higher doses in 24%. The reduction in the disease activity score was significantly greater (mean -0.4; p = 0.0085) in the adherent group than in the "low dose" group; the "high dose" group did not differ from the adherent group. Dropout caused by severe adverse events did not differ between the three groups. CONCLUSIONS: There is an indication that adherence to guidelines on methotrexate dosage may benefit patients with rheumatoid arthritis by improving disease activity without increasing toxicity. For definite proof, a randomised controlled trial comparing guideline supported dosing with usual care is needed. | |
| 15142273 | Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment. | 2004 | The aim of the present study was to investigate the effect of long-term infliximab treatment on various autoantibodies in patients with rheumatoid arthritis. Serum samples from 30 consecutive patients, who were prospectively followed during infliximab and methotrexate therapy for refractory rheumatoid arthritis, were tested at baseline and after 30, 54 and 78 weeks. At these points, median values of the Disease Activity Score were 6.38 (interquartile range 5.30-6.75), 3.69 (2.67-4.62), 2.9 (2.39-4.65) and 3.71 (2.62-5.06), respectively. Various autoantibodies were assessed by standard indirect immunofluorescence and/or ELISA. Initially, 50% of patients were positive for antinuclear antibodies, and this figure increased to 80% after 78 weeks (P = 0.029). A less marked, similar increase was found for IgG and IgM anticardiolipin antibody titre, whereas the frequency of anti-double-stranded DNA antibodies (by ELISA) exhibited a transient rise (up to 16.7%) at 54 weeks and dropped to 0% at 78 weeks. Antibodies to proteinase-3 and myeloperoxidase were not detected. The proportion of patients who were positive for rheumatoid factor (RF) was similar at baseline and at 78 weeks (87% and 80%, respectively). However, the median RF titre exhibited a progressive reduction from 128 IU/ml (interquartile range 47-290 IU/ml) to 53 IU/ml (18-106 IU/ml). Anti-cyclic citrullinated peptide (CCP) antibodies were found in 83% of patients before therapy; anti-CCP antibody titre significantly decreased at 30 weeks but returned to baseline thereafter. In conclusion, the presence of anti-double-stranded DNA antibodies is a transient phenomenon, despite a stable increase in antinuclear and anticardiolipin antibodies. Also, the evolution of RF titres and that of anti-CCP antibody titres differed during long-term infliximab therapy. | |
| 12508389 | Patient compliance in rheumatoid arthritis, polymyalgia rheumatica, and gout. | 2003 Jan | OBJECTIVE: (1) To explore patient compliance with prescribed drug regimens in the setting of usual care for outpatients with rheumatoid arthritis (RA), gout, and polymyalgia rheumatica (PMR) by utilizing electronic medication event monitors (MEMS(R)) to register openings of the medication package. (2) To examine the influence of disease, frequency of intake of the drug, and class of drug on compliance. (3) To explore the influence of demographic factors, quality of life measures, coping, health status, and functional ability as potential predictors of patient compliance. METHODS: A total of 127 consenting consecutive patients were enrolled: 81 patients with RA, 33 taking nonsteroidal antiinflammatory drugs (13 diclofenac TID and 20 naproxen BID) and 48 taking disease modifying antirheumatic drugs [25 sulfasalazine (SSZ) BID and 23 methotrexate (MTX) once weekly]; 17 patients with PMR starting with prednisolone QD; and 29 patients with gout starting with colchicine (12, QD) or starting with uric acid lowering agents (17, QD). All patients received first prescriptions and were instructed to take the medication as prescribed. Followup was 6 months (gout 12 mo). All patients were aware of the monitoring capability of the package. At baseline a series of questionnaires was completed. We summarized the dosing histories as "taking compliance" (percentage of total prescribed doses taken), "correct dosing" (percentage of doses taken as prescribed), and "timing compliance" (percentage of doses taken within +/- 25% of prescribed interdose intervals). RESULTS: A total of 26,685 days (> 73 patient-years) were monitored. Compliance expressed as "taking compliance," mean (95% CI), "correct dosing," mean (95% CI), and "timing compliance," mean (95% CI) are: naproxen: 82% (75-90), 68% (57-80), 48% (34-61); diclofenac: 77% (61-93), 67% (47-87), 39% (21-57); MTX: 107% (98-117), 81% (75-87), 83% (76-90); SSZ: 72% (60-84), 55% (44-67), 25% (18-33); prednisolone: 96% (89-102), 88% (83-92), 82% (74-89); colchicine: 65% (48-81), 44% (26-62), 32% (18-46); and uric acid lowering agents: 84% (76-92), 74% (63-85), 65% (52-79). Missed doses occurred more frequently than taking of extra doses: in RA, on 10% of all monitored days there was no evidence of dosing, while on 3% of all monitored days extra doses were taken. In PMR and gout these data are 10% and 4%, and 15% and 7%, respectively. We observed a decline of compliance over time in all study medication groups. Multiple regression analyses showed that the class of medication (symptom modifying or disease controlling), the dosing frequency, the patient's sex, coping pattern (avoidance, passive reaction pattern, and expression of emotions), and the overall health (total Nottingham Health Profile score) together explained 67% of the variance in taking compliance (adjusted R2) (p = 0.002). CONCLUSION: Studying patient compliance with prescribed drug regimens utilizing electronic medication event monitors in RA, gout, and PMR showed that large differences exist in compliance between the various medication groups. Compliance declines over time. A regression model shows that it is possible to relate differences in patient compliance to a number of medication and patient related factors. | |
| 15230130 | [Markov model of decision making for basic therapy of rheumatoid arthritis: oder of monoth | 2004 | AIM: To design Markov's model of decision making to study the role of order in the use of most usable basic antirheumatic drugs (methotrexate-MT, parenteral gold--PG and sulfasalasine--SS) in terms of the course duration and cost. MATERIAL AND METHODS: The model was based on metaanalysis made in 2000. The program TreeAge 3.0 was used. The prices for the drugs were taken as mean about Moscow for 2002 and prices presented by ACR for 2002. RESULTS: The sequence MT-PG-SS had the advantage over the other sequences in that less number of patients stopped treatment after 5 and 10 years of therapy. Mean cost of the drugs per patient is the lowest (for five years) if MT is prescribed first. In longer treatment SS-MT-PG is more cost-effective. CONCLUSION: It is feasible to design Markov's models for making decision on optimal therapy of rheumatoid arthritis both in terms of cost and clinical response. | |
| 12115159 | Physician treatment preferences in rheumatoid arthritis of differing disease severity and | 2002 Jun 15 | OBJECTIVE: To conduct a pilot study to identify rheumatologists' treatment preferences for first-line rheumatoid arthritis (RA) therapy and determine whether pharmacoeconomic variables modify physician choice(s). METHODS: A questionnaire describing 3 different RA scenarios was mailed to American College of Rheumatology members within 4 geographic regions of the US. Physicians were asked to identify their choice(s) of first-line therapy for each of the cases, first taking cost into consideration, second without considering the influence of cost, and third identifying the therapy that would be chosen for either themselves or a family member. RESULTS: Three hundred seventy-five questionnaires out of a total of 994 (37.7%) were returned between 3/12/00 and 4/25/00. Hydroxychloroquine was the most commonly cited medication for a mild disease activity/severity presentation, and methotrexate for a moderate-to-severe disease activity/severity presentation. For the severe disease activity/severity presentation, when cost was not considered, 217 (65%) rheumatologists included new disease-modifying antirheumatic drugs (leflunomide, etanercept, and infliximab) in their choice of first-line agents; this number decreased to 47 (14%) when cost was a consideration. CONCLUSION: Pharmacoeconomics appear to play a dominant role in rheumatologists' choice of treatment regimens, at times contrary to the physician's perception of the effectiveness of a drug. Future studies should address physician preferences in more depth with respect to cost and its various components. | |
| 12796204 | Methotrexate-induced pulmonary lymphoma. | 2003 Jun | Methotrexate has proven to be effective in treating rheumatoid arthritis (RA), and is believed to be nononcogenic in the low weekly dose typically employed in the patients with RA. We report, however, a patient with RA in whom a rapidly enlarging diffuse large B-cell lymphoma developed in the left upper lung after weekly treatment with methotrexate for 5 years. The patient had a positive serum IgG for Epstein-Barr virus but a negative in situ hybridization of the resected specimen. Methotrexate therapy was discontinued, and the patient elected for clinical observation instead of chemotherapy or radiation therapy. There has been no clinically detectable recurrence of the lymphoproliferative disorder for 2 years. We believe that methotrexate has an oncogenic potential even in low weekly dosing in a subset of patients with RA and latent Epstein-Barr virus infection. The strongest causal link is demonstrated by the persistent tumor remission after stopping treatment with methotrexate. | |
| 15516150 | Durability and rapidity of response to anakinra in patients with rheumatoid arthritis. | 2004 | Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease that ultimately leads to disability and functional decline. Because patients usually develop RA in mid-life, they may experience its consequences for 20-30 years or longer. Proinflammatory cytokines, notably interleukin (IL)-1 and tumour necrosis factor-alpha, are believed to play significant pathophysiological roles. Clinical trials of biologicals that block these cytokines confirm their importance.Anakinra, a recombinant human IL-1 receptor antagonist, improves clinical signs and symptoms, and slows radiographic progression in patients with active RA. In clinical trials, patients receiving anakinra doses >1 mg/kg, whether administered alone or in combination with methotrexate, were two to three times more likely than patients receiving placebo to achieve a sustained ACR20 (American College of Rheumatology criteria) response. Notably, bone erosion slows to a greater extent and shows accelerated benefit when anakinra treatment is continued for periods beyond 24 weeks. Anakinra has a rapid onset of action, with substantial improvements in biochemical indices (C-reactive protein) seen within 1 week and clinical responses (ACR20 or joint counts) seen within 4 weeks of starting treatment. Anakinra is generally well tolerated, with injection site reactions being the most common adverse event. These reactions are generally mild and typically resolve within 2-3 weeks of treatment. The anakinra product labelling does include a warning regarding an increased risk of infections of 2% in anakinra-treated patients versus <1% in patients receiving placebo. | |
| 12154206 | Analysis of improvements, full responses, remission and toxicity in rheumatoid patients tr | 2002 Aug | OBJECTIVE: To evaluate two monotherapies followed by step-up combination therapy with two or three complementary drugs in active rheumatoid arthritis (RA) in comparison with sulphasalazine (SSZ) alone. METHODS: One hundred and twenty-six consecutive patients with early active RA were enrolled in this open controlled clinical trial. The primary end-point was 50% improvement according to the ACR criteria (ACR50) at 6, 12 or 18 months. The secondary end-points were a full response (Magnusson criteria) and/or remission (ACR criteria) at 3 yr. Methotrexate (MTX) (group 1), cyclosporin A (CsA) (group 2) or SSZ (group 3) was used first. After 6 months, a combination of two drugs (CsA and MTX) was employed in groups 1 and 2. SSZ was added after 12 months if improvement was less than ACR50 with the combination. Group 3 continued with SSZ alone. RESULTS: After 6 months, 57% of patients in group 1, 31% of group 2 (MTX vs CsA, P=0.002) and 33% of group 3 (MTX vs SSZ, P=0.01) had reached ACR50 improvement according to intention-to-treat analysis. At month 12 after starting a drug combination, 67% of group 1 and 76% of group 2 had reached ACR50 compared with 24% of group 3. At the 18-month follow-up, 90% of group 1 and 88% of group 2 but only 24% of group 3 had reached ACR50. After 18 months, 62% of group 1, 60% of group 2 and 48% of group 3 showed side-effects and three, five and eight patients in the three groups respectively had dropped out of the study. At the 3-yr follow-up, 9% of the patients in groups 1 and 2 and 7% of group 3 were in remission according to the ACR criteria; according to the Magnusson criteria, 40% showed a full response in groups 1 and 2 but only 21% did so in group 3. CONCLUSION: MTX appears to be the fastest-acting agent. A step-up approach with MTX plus CsA plus SSZ led to a 50% improvement according to the ACR criteria in most patients. After 3 yr, 40% of patients receiving combination therapy and 21% of patients receiving monotherapy showed a full response, while 9 and 7% respectively attained remission. | |
| 15110230 | P-glycoprotein in autoimmune diseases. | 2004 Mar | Multidrug resistance-1 (MDR-1) is characterized by overfunction of P-glycoprotein (P-gp), a pump molecule that decreases intracellular drug concentration by effluxing them from the intracellular space. Broad ranges of structurally unrelated compounds are transported by P-gp, including antineoplastic agents, HIV protease inhibitors, prednisone, gold salts, methotrexate, colchicine as well as several antibiotics. In contrast, many other compounds such as calcium channel blockers (verapamil) and immunosupressors (cyclosporine-A) are able to inhibit P-gp function. The P-gp role in therapeutic failures has been extensively studied in cancer; however, there is little information regarding MDR-1 phenotype in autoimmune disorders. It has been reported that an increased number of lymphocytes are able to extrude P-gp substrates in rheumatoid arthritis, immune thrombocytopenic purpura and systemic lupus erythematosus, the patients with poor response to treatment being the ones that exhibit the highest values. This may be due, at least in part, to a simultaneous long-term usage of several drugs that induce P-gp function. Since abnormally activated cell compartments characterize autoimmune diseases, it is possible that those cells are the ones that exhibit drug resistance. The study of drug resistance mechanisms in autoimmunity may be helpful for the optimization of the current therapeutic schemes through their combination with low doses of P-gp inhibitors. | |
| 12379627 | Infliximab treatment for rheumatic disease: clinical and radiological efficacy. | 2002 Nov | Infliximab is a chimeric anti-tumour necrosis factor alpha (TNFalpha) monoclonal antibody with high affinity and binding specificity for human TNFalpha. Results from several well designed, controlled clinical trials show repeated infusions of infliximab with concomitant methotrexate (MTX) treatment can reduce the signs and symptoms of rheumatoid arthritis (RA). This combination of infliximab and MTX also slows the radiological progression of joint damage, decreases functional disability, and improves qualify of life. These remarkably positive results have led to the investigation of infliximab treatment for other rheumatic diseases. Recently, controlled studies have shown treatment with infliximab can benefit patients with active spondyloarthropathy. TNFalpha has fast become an important therapeutic target in rheumatology. |