The aryl hydrocarbon receptor (AHR) is well known for mediating the toxic effects of TCDD and has been a subject of intense research for over 30 years. Current investigations continue to uncover its endogenous and regulatory roles in a wide variety of cellular and molecular signaling processes. A zebrafish line with a mutation in ahr2 (ahr2(hu3335)), encoding the AHR paralogue responsible for mediating TCDD toxicity in zebrafish, was developed via Targeting Induced Local Lesions IN Genomes (TILLING) and predicted to express a non-functional AHR2 protein. We characterized AHR activity in the mutant line using TCDD and leflunomide as toxicological probes to investigate function, ligand binding and CYP1A induction patterns of paralogues AHR2, AHR1A and AHR1B. By evaluating TCDD-induced developmental toxicity, mRNA expression changes and CYP1A protein in the AHR2 mutant line, we determined that ahr2(hu3335) zebrafish are functionally null. In silico modeling predicted differential binding of TCDD and leflunomide to the AHR paralogues. AHR1A is considered a non-functional pseudogene as it does not bind TCCD or mediate in vivo TCDD toxicity. Homology modeling, however, predicted a ligand binding conformation of AHR1A with leflunomide. AHR1A-dependent CYP1A immunohistochemical expression in the liver provided in vivo confirmation of the in silico docking studies. The ahr2(hu3335) functional knockout line expands the experimental power of zebrafish to unravel the role of the AHR during development, as well as highlights potential activity of the other AHR paralogues in ligand-specific toxicological responses.
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Among the 407 selected patients, 378 patients were included in the study, all of whom were treated with leflunomide. Female patients made up 78.6% of the study population; the mean age was 57.7 +/- 12.0 years, and the mean disease duration was 9.7 +/- 8.5 years. At 6 months, the ACR 20 response rate was 48.2% (95% confidence interval [CI] 43-53%). ACR 50 and 70 response rates were 25.3% (95% CI 21.0-30.1) and 11.7% (95% CI 8.6-15.4%), respectively. According to the DAS28, 21.8% of patients had a good response, 39.9% a moderate response, and 38.2% were non-responders. The DAS28 response rate was thus 61.8% (95% CI 56.5-66.9%). Mean improvements in tender joint count were -5.6 +/- 7.4 (from baseline of 12.2 +/- 6.7), in swollen joint count were -4.2 +/- 5.7 (from baseline of 9.8 +/- 5.8), and in investigator's global assessment of RA disease activity were -20.2 +/- 25.1 (from baseline of 51.6 +/- 17.1). Treatment-related adverse events caused 15.9% of patients to discontinue the study prematurely. Serious adverse events possibly related to therapy were reported in 2.4% of patients.
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Leflunomide pretreatment significantly ameliorated pancreatic hemorrhage, edema, and neutrophil infiltration and decreased histopathological score compared with the untreated severe necrotizing pancreatitis group (pathological score [mean +/- SEM]: 6.70 +/- 1.19 vs 12.36 +/- 1.08 in the leflunomide treated and untreated groups, respectively, P < 0.01). Pulmonary changes was decreased in the leflunomide treated group (3.90 +/- 0.45 vs 4.75 +/- 0.25, respectively). Change in pulmonary alveolar distention was significant. Although serum amylase levels also decreased, the difference was not significant (5922 +/- 3290 vs 15547 +/- 5090 U/mL).
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A total of 1093 patients were included. Eighty-five percent were female, and 76% had a positive rheumatoid factor. Mean age at diagnosis was 46.5 (SD, 14.2) years, and mean disease duration at the first visit was 5.8 (SD, 3.8) months. Between baseline and second visit (3 months), 75% of patients (95% CI, 72%-78%) received disease-modifying antirheumatic drugs. Methotrexate (MTX) alone or in combination was the most frequently used (60.5%), followed by antimalarials (chloroquine or hydroxychloroquine, 32.1%), sulfasalazine (7.1%), and leflunomide (LEF, 4%). In 474 patients (43%), initiation of disease-modifying antirheumatic drugs was within the first month after the first visit. In addition, 290 patients (26%; 95% CI, 23%-29%) received combination therapy as initial treatment. The most frequently used combinations were MTX + chloroquine (45%), MTX + hydroxychloroquine (25%), and MTX + sulfasalazine (16%). Eleven patients (1%; 95% CI, 0.5%-1.8%) received biologics. Sixty-four percent (95% CI, 60%-66%) received corticosteroids. Of those, 80% (95% CI, 77%-84%) received 10 mg of oral prednisone or less.
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Peripheral blood mononuclear cells (PBMC) from 12 healthy volunteers were isolated by density separation over Ficoll solution. After resuspension in adaptive immunotherapy medium (AIM)-V medium, they were cultured without exogenous growth factors. The study group was treated with FK 778 (50 microg/mL) or Rapamycin (10 ng/mL). The phenotype of dendritic cell was ascertained by indirect immunoflurescence for analysis by flow cytometry.
Although many viruses produce musculoskeletal symptoms during an acute infection, a long-term inflammatory arthritis remains an unusual consequence. When evaluating arthritis in a patient with a chronic or latent viral infection, serologic testing and therapeutic options are significantly altered.
To summarize the therapeutic options for proliferative and membranous lupus nephritis that is resistant to conventional treatment.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, adding calcipotriol (topical) to psoralen plus ultraviolet light A or ultraviolet light B, adding oral retinoids to psoralen plus ultraviolet A (PUVA), alefacept, balneotherapy, ciclosporin, dithranol, T cell-targeted therapies, cytokine blocking agents, emollients (alone or plus ultraviolet light B), etanercept, fish oil supplementation, fumaric acid derivatives, Goeckerman treatment, heliotherapy, infliximab, Ingram regimen, keratolytics (salicylic acid, urea), leflunomide, methotrexate, oral pimecrolimus, phototherapy plus balneotherapy, psoralen plus ultraviolet A, psychotherapy, oral retinoids (alone or with ultraviolet light B), systemic drug treatments plus topical vitamin D derivatives, tars, tazarotene, topical corticosteroids (alone or plus oral retinoids), topical Vitamin D derivatives, ultraviolet light A, and ultraviolet light B.
During the study period 136 rheumatoid arthritis patients started leflunomide. Median (range) follow-up duration was 317 (11-911) days. Sixty-five percent of patients experienced at least one adverse drug reaction related to leflunomide. During follow-up 76 patients (56%) withdrew from leflunomide treatment, mainly because of adverse drug reactions (29%) or lack of efficacy (13%). The overall incidence density for withdrawal from leflunomide was 56.2 per 100 patient-years. Complete data for calculating efficacy using a validated disease activity score on 28 joints (DAS(28)) was available for 48, 36, and 35% of patients at 2, 6, and 12 months follow-up, respectively. Within a 12-month period after start of leflunomide treatment 76% of the evaluable patients were classified as moderate or good responders according to the DAS(28) response criteria.
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Leflunomide inhibits the division of activated T cells and thus inhibits among others the production of proinflammatory cytokines and the adhesion of cells to the endothelium. These mechanisms may partly explain the possible influence of leflunomide on the perpetuation of the ulcer. Until now, occurrence of vasculitis and leg ulcers has been described in one case each for the novel immunomodulator leflunomide. No successful treatment of a leg ulcer under leflunomide has been described yet. Omission of leflunomide and a washout treatment in our case led to a complete healing. This may indicate a critical role of leflunomide in the maintenance of this slow healing ulcer.
To calculate the number needed to treat (NNT) and number needed to harm (NNH) from the data in rheumatology clinical trials and systematic reviews.
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In a world of diminishing water reservoirs and a rising demand for food, the practice and development of water stress indicators and sensors are in rapid progress. The heat dissipation method, originally established by Granier, is herein applied and modified to enable sap flow measurements in date palm trees in the southern Arava desert of Israel. A long and tough sensor was constructed to withstand insertion into the date palm's hard exterior stem. This stem is wide and fibrous, surrounded by an even tougher external non-conducting layer of dead leaf bases. Furthermore, being a monocot species, water flow does not necessarily occur through the outer part of the palm's stem, as in most trees. Therefore, it is highly important to investigate the variations of the sap flux densities and determine the preferable location for sap flow sensing within the stem. Once installed into fully grown date palm trees stationed on weighing lysimeters, sap flow as measured by the modified sensors was compared with the actual transpiration. Sap flow was found to be well correlated with transpiration, especially when using a recent calibration equation rather than the original Granier equation. Furthermore, inducing the axial variability of the sap flux densities was found to be highly important for accurate assessments of transpiration by sap flow measurements. The sensors indicated no transpiration at night, a high increase of transpiration from 06:00 to 09:00, maximum transpiration at 12:00, followed by a moderate reduction until 08:00; when transpiration ceased. These results were reinforced by the lysimeters' output. Reduced sap flux densities were detected at the stem's mantle when compared with its center. These results were reinforced by mechanistic measurements of the stem's specific hydraulic conductivity. Variance on the vertical axis was also observed, indicating an accelerated flow towards the upper parts of the tree and raising a hypothesis concerning dehydrating mechanisms of the date palm tree. Finally, the sensors indicated reduction in flow almost immediately after irrigation of field-grown trees was withheld, at a time when no climatic or phenological conditions could have led to reduction in transpiration.
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This study of leflunomide in patients using the drug clinically indicated a concentration-effect relationship. From our data, a plasma A77 1726 concentration of 50 mg l(-1) is more likely to indicate someone with less active disease than is a concentration around 30 mg l(-1). The marked variability in pharmacokinetics suggests a place for individualized dosing of leflunomide in RA therapy.
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Between January 2002 and December 2004, 54 new BP patients were diagnosed in the Limoges Department of Dermatology: 18 male and 36 female, median age 84 years. Forty patients were treated with superpotent topical CS, 14 required adjuvant immunosuppressant treatment (oral CS, methotrexate, dapsone, mycophenolate mofetil, leflunomide). Over the first 6 months, 28 patients could not be further investigated due to death (n = 20) or loss to follow-up (n = 8). In the 26 patients evaluable for treatment efficacy at month 6, control of the disease was achieved in 17 patients, and nine relapses were seen. The one-year Kaplan-Meier survival rate was 56%. Among the 23 patients evaluable at month 12, control of disease was achieved in 13 patients (complete remission without treatment, n = 2; remission with immunosuppressant treatment, n = 8). Therapeutic failure was concluded for 16 patients, eight of whom presented two relapses during the first year of follow-up.
C57BL/6 mice were given 2 Gy total-body irradiation, followed by an intravenous injection of 2 × 10(7) BALB/c bone marrow cells (BMCs). Mice were treated with LEF daily at a dose of 30 mg/kg/day for 2 weeks.
This was an open labeled, randomized, comparative clinical trial in the department of rheumatology and immunology, at a tertiary care center in Bangalore. Patients who have diagnosed with rheumatoid arthritis as per American College of Rheumatology aged between 18 and 60 years were recruited and randomized to receive leflunomide (10 mg/day p.o.) or a combination of methotrexate and hydroxychloroquine (7.5 mg/week p.o. and 200 mg/day p.o., respectively) along with folate supplementation for 12 weeks. The European League Against Rheumatism criteria of improvement according to disease activity score 28 was considered as the primary efficacy variable. Baseline and end of study values were evaluated. The duration of the study period was 1 year. Analysis of variance (ANOVA) and Wilcoxon Signed rank test were used for statistical analysis.
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A retrospective cohort study at a vasculitis referral centre was performed. All EGPA patients admitted from 1990 to 2009 were included. A structured interdisciplinary work-up for proof of diagnosis, Disease Extent Index and Birmingham Vasculitis Activity Score was performed. Immunosuppressive therapy was initiated and regularly adapted. Treatment targets were induction and maintenance of remission according to definitions given by the European League Against Rheumatism and the European Vasculitis Study Group. Outcomes were mortality, rate of remission, relapses, adverse events and prednisolone-dose.
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We report the unique occurrence and treatment of spontaneous multiple insufficiency fractures after sepsis in a patient with rheumatoid arthritis (RA). The patient was a 53-year-old woman with a 13-year history of RA. Her disease activity was not influenced by a disease-modifying antirheumatic drug (DMARD) regimen that included bucillamine, D-penicillamine, gold, sulfasalazine, and methotrexate. Due to an increased disease activity, her DMARD treatment regimen was changed to leflunomide. She had also undergone corticosteroid therapy with prednisolone ranging from 10 to 15 mg daily over the previous 8 years. She first presented with a wound infection at the surgical site of resection arthroplasty on her left foot, which had caused hematogenous dissemination that led to pelvic abscess and sepsis. For the next 2 years, she experienced multiple insufficiency fractures in parts of the ilium, sacral body, sacral ala, three thoraco-lumbar vertebral bodies (T12, L1, and L2), and subcapital femoral neck without low energy trauma. Postmenopausal osteoporosis, pelvic abscess, sepsis, decreasing daily activity, high RA disease activity, and high-load corticosteroid therapy were considered to be the causes of these fractures. Nonspecific symptoms such as low back pain and fever delayed diagnosis, which may have led to secondary fractures. Although her course after treatment was satisfactory during the study period, we recommend taking repetitive radiographs to detect insufficiency fracture for RA patients with continuing pain and reducing the corticosteroid dose to prevent infection and fracture.
During a screen for molecules that activate the AhR, leflunomide, an immunomodulatory drug presently used in the clinic for the treatment of rheumatoid arthritis, was identified as an AhR agonist. We aimed to determine whether any biological activity of leflunomide could be attributed to a previously unappreciated interaction with the AhR. The currently established mechanism of action of leflunomide involves its metabolism to A771726, possibly by cytochrome P450 enzymes, followed by inhibition of de novo pyrimidine biosynthesis by A771726. Our results demonstrate that leflunomide, but not its metabolite A771726, caused nuclear translocation of AhR into the nucleus and increased expression of AhR-responsive reporter genes and endogenous AhR target genes in an AhR-dependent manner. In silico Molecular Docking studies employing AhR ligand binding domain revealed favorable binding energy for leflunomide, but not for A771726. Further, leflunomide, but not A771726, inhibited in vivo epimorphic regeneration in a zebrafish model of tissue regeneration in an AhR-dependent manner. However, suppression of lymphocyte proliferation by leflunomide or A771726 was not dependent on AhR.
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Together with CsA, the new macrolide immunosuppressants FK506 and rapamycin have proved to be valuable tools in providing new information about key molecular events that underlie lymphocyte activation and degranulation. Studies of their mechanisms of action have pinpointed the phosphatase calcineurin and protein kinases as important signaling mediators in T-cell activation. Other new immunosuppressive drugs, including leflunomide, mycophenolate mofetil, brequinar sodium and deoxyspergualin exhibit diverse inhibitory effects on cells of the immune system and offer considerable promise as adjunctive therapeutic immunosuppressants. FK506 appears to be both a valuable therapeutic alternative to liver or kidney retransplantation and an alternative primary immunosuppressant to CsA in hepatic (especially) and renal transplantation. There is now good evidence that immunosuppressive drugs, both old and new, permit the establishment of donor-derived, multi-lineage cell chimerism following organ transplantation.
Glucocorticoids play a pivotal role in the management of RA. This is reflected in the extensive use of low-dose glucocorticoids by German rheumatologists. Even if highly effective DMARDs are prescribed, they are accompanied by glucocorticoids, at least in the initial phase. High-dose glucocorticoids are prescribed for only a small proportion of the patients. There is increasing awareness of the risk of osteoporosis in long-term glucocorticoid treatment, demonstrated by the fact that osteoporosis medication is prescribed for a large proportion of patients taking glucocorticoids.
Methotrexate is currently one of the most widely prescribed disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA). Combination therapy of methotrexate with other DMARDs increases the clinical success of low-dose methotrexate treatment. Leflunomide is a new DMARD that may have a high potential for success in combination therapy with methotrexate. This review compares the mode of action of methotrexate and leflunomide and speculates on how this contributes to therapeutic efficacy in RA when these agents are used singly or in combination.
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A systematic review of the literature using PubMed, Embase and the Cochrane library was performed up to January 2009. All randomised controlled trials (RCTs) reporting the efficacy of synthetic DMARDs (vs placebo or other synthetic DMARDs) on signs and symptoms, disability and/or radiographic structural damage in patients with RA were selected. Studies of biological agents or glucocorticoids were excluded. A pooled effect size (ES) was calculated by meta-analysis. Safety and the occurrence of infections and neoplasia was also assessed.
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LEF (0.3, 3, and 9 micro g/ml) inhibited IL1beta production in the presence of lipopolysaccharide (LPS; 3 micro g/ml) in a dose dependent manner (p<0.01) at LEF 0.3 micro g/ml. TNFalpha production in the presence of IL1beta (1 ng/ml) was also inhibited in a dose dependent manner (p<0.05 at LEF 0.3 micro g/ml). NO and MMP-3 production in the presence of LPS (3 micro g/ml) was inhibited as well (p<0.01 at LEF 1 micro g/ml and at LEF 0.3 micro g/ml, respectively). Synovial cell viability evaluated by the tetrazolium salt XTT was unaffected by the LEF concentration used. There was no qualitative difference in the response of OA and RA synovial tissue.
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For most new disease-modifying biologic medications, we have few data on safety. More and more reassuring data are accumulating on azathioprine and cyclosporine. When you treat this patient, you can help in gathering such data by contacting the Organization of Teratology Information Specialists' Autoimmune Disease in Pregnancy study through Motherisk at 877 311-8972.
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OA synoviocytes were cultured under different concentrations of IL13. Periostin content in culture supernatants and the level of signal transducer and activator of transcription 6 (STAT6) in the cultured cells were measured using enzyme-linked immunosorbent assay (ELISA). Moreover, the influence of dexamethasone and leflunomide on periostin production in relation to the effect of IL13 on the cells was also examined.
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CYP1A2 is one of the major CYPs in human liver ( approximately 13%) and metabolises a variety of clinically important drugs, such as clozapine, lidocaine, theophylline, tacrine, and leflunomide. CYP1A2 is one of the major enzymes that bioactivate a number of procarcinogens and thus induction of CYP1A2 may increase the carcinogenicity of these compounds. This enzyme also metabolizes several important endogenous compounds including steroids, retinols, melatonin, uroporphyrinogen and arachidonic acid. In the recently published crystal structure of CYP1A2 in complex with alpha-naphthoflavone, its compact active site is closed without clear solvent or substrate access channels. Not surprisingly, CYP1A2 has a relatively small volume of the active site cavity of 375 A(3), which is 44.2% larger than that of CYP2A6 (260 A(3)), but much smaller than that of CYP3A4 (1385 A(3)) and 2C8 (1438 A(3)). Generally, CYP1A2 substrates contain planar ring that can fit the narrow and planar active site of the enzyme. Like many of other CYPs, CYP1A2 is subject to induction and inhibition by a number of compounds. Similar to CYP1A1 and 1B1, CYP1A2 is primarily regulated by the aromatic hydrocarbon receptor (AhR), a ligand-activated transcription factor and a basic helix-loop-helix protein belonging to the Per-Arnt-Sim family of transcription factors. Knockout of Cyp1a2 in mice has provided a very useful tool for the functional investigation of this gene. Further studies are needed to explore the clinical and toxicological significance of CYP1A2.
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Juvenile idiopathic arthritis (JIA) comprises a group of heterogeneous disorders of chronic arthritis in childhood and remains the commonest pediatric rheumatic disease associated with significant long-term morbidity. Advances in understanding of the pathogenesis, better definition of disease control/remission measures, and the arrival of biological agents have improved the outcomes remarkably. Methotrexate (Mtx) remains the first-line disease modifying (DMARD) therapy for most children with JIA due to its proven efficacy and safety. Sulphosalazine (SSz) (especially for enthesitis) and leflunomide may also have a secondary role. Tumor necrosis factor inhibitors (TNF-I), alone or in combination with Mtx have shown tremendous benefit in children with polyarticular JIA, enthesitis related arthritis (ERA) and psoriatic arthritis. Tocilizumab appears very efficacious in systemic arthritis and abatacept and tocilizumab also appear to benefit polyarticular JIA; the role of rituximab remains unclear, though clearly beneficial in adult RA. TNF-I with Mtx is also effective in uveitis associated with JIA. Biologicals have demonstrated an impressive safety record in children with JIA, although close monitoring for rare but potentially dangerous adverse events, such as tuberculosis and other infections; paradoxical development of additional autoimmune diseases; and possibly an increased risk of cancers is warranted.
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Till now there has not been reported data related to the influence of leflunomide on the thyroid gland function of the treated person. The authors described the case of woman with rheumathoid arthritis and hypothyroidism who revealed hyperthyroidism in 7 months after starting leflunomide tablets treatment containing povidone iodine as well. Also both autonomical tissue area in thyroid right lobe and hight TSHRAb level were found. Leflunomid tablets containing povidone iodine in its structure can cause hyperthyroidism in the person with previous hypothyroidism and nodular goiter, probably as a result of immunological reconversion and tissue nodular functional autonomisation. In persons with nodular goitre one should prefer free of povidone iodine leflunomide treatment and also monitor serum thyroid hormone contents and thyroid antibodies as well.
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To evaluate the relative risk (RR) of pulmonary disease among patients with rheumatoid arthritis (RA) treated with leflunomide (LEF).