Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
17332143 Effect of DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopy 2007 Jun DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] is a potent human tumor necrosis factor alpha-converting enzyme inhibitor with potential therapeutic implications for rheumatoid arthritis. Methotrexate (MTX), a drug for the treatment of rheumatoid arthritis, is eliminated primarily unchanged via renal and biliary excretion in humans as well as in rats and dogs. The objective of the present study was to investigate the potential effect of DPC 333 on the disposition of MTX. In dogs, DPC 333 administered orally at 1.7 mg/kg 15 min before the intravenous administration of [14C]MTX (0.5 mg/kg) did not alter the plasma concentration-time profile of MTX; however, the total amount of radioactivity excreted in urine increased from 58.7% to 92.2% of the dose, and the renal clearance increased from 1.8 ml/min/kg to 2.9 ml/min/kg, suggesting a decrease in MTX disposition via biliary excretion. The biliary excretion of MTX was investigated in isolated perfused livers prepared from wild-type and TR(-) [multidrug resistance-associated protein 2 (Mrp2)-deficient] Wistar rats in the absence and presence of DPC 333. Mrp2-mediated biliary excretion of MTX was confirmed with 95.8% and 5.1% of MTX recovered in the bile of wild-type and TR(-) Wistar rats, respectively. DPC 333 at an initial perfusate concentration of 50 microM completely blocked the biliary excretion of MTX, but not the clearance from perfusate, in both wild-type and TR(-) rats. These results suggest that the enhanced renal elimination of MTX may be due to the potent inhibition of biliary excretion and active renal reabsorption by DPC 333 and/or its metabolites.
16750873 [Evolution and prognosis of adult onset Still's disease. A monocentric study of 17 patient 2006 Sep Adult-Onset Still's disease (AOSD) is a rare condition of unknown origin with various presentations and unpredictable outcome. The aim of this study was to analyse clinical and biological presentation, and outcome of patients admitted to an internal medicine service. METHOD: A retrospective cohort design with prospective follow-up was used. All the patients admitted to our internal medicine service for AOSD between January 1998 and March 2004 were included. RESULTS: According to Yamaguchi's classification criteria, 17 patients were analysed with a mean age at onset of 37.3 years and a 2.4 sex-ratio (female/male). Mean follow-up length was 52.1 months. Eight patients developed a monocyclic systemic form, 8 a polycyclic systemic form and 1 a chronic articular form. Arthralgia (87%) and arthritis (53%) were less frequent than in other series. Sixteen patients were treated: 14 by corticosteroids, 6 by non-steroid anti-inflammatory drugs, 5 by methotrexate, 2 intravenous polyglobulin and one by anti-TNF drug. Patients with a corticodependant or corticoresistant form had more polyarthritis at the onset of the disease (3/6 vs 0/11, P=0.029). DISCUSSION: In internal medicine activity, AOSD without oligo- or polyarthritis may be more frequent than expected according to the literature. Corticotherapy alone is often efficient in these AOSD form without synovitis, and methotrexate use is uncommon.
17185324 Efficacy of infliximab on MRI-determined bone oedema in psoriatic arthritis. 2007 Jun BACKGROUND: Psoriatic arthritis (PsA) is commonly associated with bone pathology, including entheseal new bone formation and osteolysis. On MRI, areas of active clinical involvement are represented by bone oedema and synovitis. AIM: To assess the impact of infliximab on bone oedema in PsA as shown by MRI. METHODS: 18 patients with joint swelling, psoriasis and seronegativity for rheumatoid factor received four infusions of infliximab, 3 mg/kg, in combination with methotrexate. MRI of the affected hand (12 patients) or knee joints (6 patients) was performed before and after treatment. The primary outcome was the assessment of bone oedema and synovitis at 20 weeks as shown by MRI. Secondary outcomes included the American College of Rheumatology (ACR) response criteria, psoriasis skin scores (Psoriasis Area and Severity Index (PASI)) and a quality of life measure (Psoriatic Arthritis Quality of Life (PsAQoL)). RESULTS: At baseline, bone oedema was seen in 50% of patients (seven hands and two knees) in 30% of scanned joints, and this improved or resolved in all cases in the hand joints (p = 0.018) and in one knee joint at 20 weeks. Synovitis was found to be reduced in 90% of cases on MRI. Likewise, a significant improvement in all clinical outcomes, including PASI (p = 0.003) and PsAQoL (p = 0.006) was seen at week 20. 65% (n = 11) of the patients achieved an ACR response, of whom 45% had ACR70 or above and 54% had ACR20 or ACR50. CONCLUSIONS: Infliximab treatment is associated with dramatic improvements in MRI-determined bone oedema in PsA in the short term. It remains to be determined whether infliiximib treatment is the cause for prevention of new bone formation, bone fusion or osteolysis in PsA as shown by radiography.
17562077 Factors influencing the efficacy of intra-articular steroid injections in patients with ju 2008 Apr A retrospective chart review was performed of all patients with juvenile idiopathic arthritis (JIA) followed at our clinic who had an intra-articular steroid injection between 1 January 1997 and 31 December 2001. The aim of the study was to evaluate the outcome of intra-articular steroid injections (iaS) and determine prognostic factors. During the study period, 202 iaS were performed in 60 patients, of whom 37 had oligoarticular JIA, 15 had polyarticular, rheumatoid factor-negative JIA and four each had systemic and enthesitis-related JIA. The median duration of remission was 23.1 months (range: 0-69 months). At last follow-up, 103 joints (51%) of 47 patients were still in remission after a median follow-up time of 28 months (range: 1-69 months). For the total cohort, the remission was longer for wrist and finger joints [risk ratio (RR): 0.2], with concomitant treatment with methotrexate (RR: 0.28) and for enthesitis-related arthritis (RR: 0.34). For the group of knee joints, remission was longer with concomitant treatment with methotrexate (RR: 0.37), with triamcinolone hexacetonide (RR: 0.77) and with general anaesthesia for the procedure (RR: 0.56). Mild side effects were observed in 45 iaS (22.3%), and skin atrophy occurred at the injection site in 2% of injections, but no major adverse event occurred in our cohort. In conclusion, iaS is a safe procedure with a median duration of remission of 23.1 months. The remission was longer in the joints of the upper extremity, with concomitant treatment with methotrexate and when the injection was performed under general anaesthesia.
16947627 Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Resul 2006 Sep OBJECTIVE: To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti-tumor necrosis factor (anti-TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population. METHODS: We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multicenter, randomized, double-blind, placebo-controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti-TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks. RESULTS: Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab-treated patients than placebo-treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate-to-good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab-treated patients, who also had clinically meaningful improvements in fatigue, disability, and health-related quality of life (demonstrated by FACIT-F, HAQ DI, and SF-36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild-to-moderate severity. The rate of serious infections was 5.2 per 100 patient-years in the rituximab group and 3.7 per 100 patient-years in the placebo group. CONCLUSION: At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies.
19110071 Methotrexate-induced cytotoxicity and genotoxicity in germ cells of mice: intervention of 2009 Feb 19 Methotrexate (MTX) is an anti-metabolite widely used in the treatment of neoplastic disorders, rheumatoid arthritis and psoriasis. The basis for its therapeutic efficacy is the inhibition of dihydrofolate reductase (DHFR), a key enzyme in the folic acid (FA) metabolism. FA is a water-soluble vitamin which is involved in the synthesis of purines and pyrimidines, the essential precursors of DNA. Folinic acid (FNA) is the reduced form of FA that circumvents the inhibition of DHFR. Folate supplementation during MTX therapy for psoriasis and inflammatory arthritis reduces both toxicity and side effects without compromising the efficacy. Further, FNA supplementation reduces the common side effects of MTX in the treatment of juvenile idiopathic arthritis. FA and FNA are reported to have protective effects on MTX-induced genotoxicity in the somatic cells; however their protective effects on the germ cells have not been much explored. Previously, we evaluated the cytotoxic and genotoxic effects of MTX in the germ cells of mice. In the present study, we have intervened FA and FNA for the protection of germ cell toxicity induced by MTX in male swiss mice. The animals were pre-treated with FA at the doses of 50, 100 and 200 microg/kg for 4 consecutive days per week and on day five; MTX was administered at the dose of 20mg/kg once. FNA was administered at the doses of 2.5, 5 and 10 mg/kg, 6 h (h) after single administration of MTX at the dose of 20 mg/kg. The dosing regimen was continued up to 10 weeks. The germ cell toxicity was evaluated using testes weight (wt), sperm count, sperm head morphology, sperm comet assay, histology, TUNEL and halo assay in testis. The results clearly demonstrate that prior administration of FA and post-treatment with FNA reduces the germ cell toxicity induced by MTX as evident from the decreased sperm head abnormalities, seminiferous tubule damage, sperm DNA damage, TUNEL positive cells and increased sperm counts. In the present study, we report that FA and FNA ameliorate the germ cell toxicity of MTX in mice.
17979026 Treatment options for refractory Wegener's granulomatosis: a role for rituximab? 2007 Nov Wegener's granulomatosis (WG) is a small-vessel vasculitis of unknown etiology, involving mainly the upper airways, lungs and kidneys. Organ inflammatory damage is mediated by anti-neutrophil cytoplasm antibodies, and their detection is a component of the diagnostic work-up as well as clinical signs and symptoms, and histopathological biopsy abnormalities. Conventional therapeutic regimens, such as cyclophosphamide and corticosteroids, can be used to induce and maintain disease remission. Alternatively, other cytotoxic agents (eg, methotrexate or mycophenolate mofetil), anti-TNFalpha agents (eg, infliximab or etanercept) or anti-lymphocyte antibodies (eg, rituximab) can be used. Rituximab, a mAb which targets CD20+ B-cells, is currently used in the treatment non-Hodgkin's lymphoma and rheumatoid arthritis, and is being investigated for refractory WG therapy and other autoimmune diseases.
17452815 Immunodeficiency-related Hodgkin lymphoma and its mimics. 2007 May Classic Hodgkin lymphoma (CHL) in patients with underlying immunodeficiency disorders frequently differs from that in the immune competent population in terms of its clinical behavior and pathologic features. Moreover, differential from Hodgkin-like lymphoid proliferations may be problematic. Topics under review include: (a) CHL posttransplant lymphoproliferative disorders, (b) CHL in HIV/AIDS, (c) Hodgkin variant of Richter syndrome in chronic lymphocytic leukemia in association with fludarabine therapy, (d) CHL in other immunodeficiency states including methotrexate-associated lymphoproliferative disorder in patients with rheumatoid arthritis and primary immune deficiencies, and (e) Hodgkin-like lymphoid proliferations including senile Epstein-Barr virus+ B-cell lymphoproliferative disorder. Also under consideration is the pathogenesis of these disorders with an emphasis on the role of Epstein-Barr virus.
17040588 Etanercept, a tumour necrosis factor alpha receptor antagonist, and methotrexate in acute 2006 Dec Patients with autoimmune inner-ear disease (AIED) are treated with high doses of steroids in the short term when suffering an acute hearing loss. As a consequence, substances such as methotrexate have been employed in the role of steroid-sparing agents. Additionally, it is known that tumour necrosis factor alpha (TNFalpha) is an important mediator of the inflammatory process, inhibition of which may be of benefit in AIED. This case report illustrates the use of a TNFalpha inhibitor in combination with methotrexate, which is known to be an effective combination in rheumatoid arthritis but has yet to be described for sensorineural hearing loss. We conclude that progressive AIED may respond well to TNFalpha inhibition, whilst more difficult cases, such as this example, could benefit from combining such therapy with methotrexate.
19112768 Etanercept in therapy multiresistant overlapping pityriasis lichenoides. 2008 Oct INTRODUCTION: Pityriasis lichenoides (PL) exhibits a protean clinical presentation, particularly in its overlapping form (OPL) combining aspects of the acute and chronic types. Some patients are drug multiresistant and pose a therapeutic dilemma. The anti-tumor necrosis factor (TNF)-alpha agent etanercept, was recently introduced as an alternative treatment for psoriasis, rheumatoid arthritis, and psoriatic arthritis. CASE REPORT: A 65-year-old woman suffered from an overlapping form of pityriasis lichenoides (OPL) for 5 years. Several initial acute episodes were controlled by successive courses of oral antibiotics, topical corticosteroids, and/or psoralen ultraviolet light-A (PUVA) therapy. The disease progressively evolved to a more chronic form. Topical immune response modifiers and corticosteroids, as well as PUVA, ultraviolet light-B (UVB), methotrexate, dapsone, and cyclosporine were introduced, but all proved ineffective. Due to the therapy multiresistance, 2 weekly injections of etanercept were administered. After 2 months, a marked improvement was observed in regards to the patient's pruritus and inflammation. No treatment-related adverse effects were observed. Therapy was continued for 4 months without any new lesion development. However, 1 month after stopping treatment new OPL lesions recurred. CONCLUSION: At the time of publication, this is the first report of the effectiveness of etanercept in OPL. This drug might be considered as a therapeutic alternative for treatment multiresistant OPL.
18292102 Can clinical factors at presentation be used to predict outcome of treatment with methotre 2009 Jan PURPOSE: Methotrexate (MTX) is the first choice conventional disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. It is not universally effective, however; although to date it is not possible to predict with any accuracy which patients will respond to treatment. The aim of this analysis was to examine whether clinical and genetic variables could be used to predict response to MTX. METHODS: Patients recruited to the Norfolk Arthritis Register (NOAR), a primary care based inception cohort of patients with inflammatory polyarthritis, were eligible for this analysis if they were commenced on MTX as their first DMARD within 3 months of their baseline visit and had at least 2 years of follow-up data. Outcome on MTX was defined as: (1) stopped for adverse events; (2) stopped for inefficacy or second DMARD added; (3) stopped for other reasons; or (4) remained on MTX monotherapy. Multiple logistic regression was used to establish which variables (including demographics, disease activity and Health Assessment Questionnaire score) predicted stopping monotherapy for inefficacy or adverse event (with those remaining on treatment taken as the referent category). The area under the Receiver Operating Characteristic curves (AUC ROC), were used to determine how accurate the model was at predicting outcome. RESULTS: 309 patients were included in this analysis. At 1 year (2 years), 34 (46) patients had stopped for adverse events and 25 (49) had either stopped monotherapy for inefficacy or had a second DMARD added. 231 (188) patients remained on MTX monotherapy. The strongest predictor of inefficacy at both time points was shared epitope positivity: odds ratios (OR) 5.8 (95% confidence intervals (CI) 1.3 to 25.6) at 1 year, OR 3.0 (95% CI 1.3 to 7.3) at 2 years. High Health Assessment Questionnaire score (OR 1.84 95% CI 1.12 to 3.01) and female gender (OR 2.2, 95% CI 0.92 to 5.28) were associated with adverse events on MTX at 1 year. However, even the most optimal combinations of the factors analysed were only weakly predictive of treatment outcome: AUC ROC for adverse events 0.68 (95% CI 0.58 to 0.78) and for inefficacy AUC ROC 0.71 (95% CI 0.6 to 0.81). CONCLUSIONS: Within this cohort, routine clinical and laboratory factors were poor at predicting outcome of treatment with MTX. Given the major therapeutic advantage to be derived from accurate prediction of treatment outcome, further studies will need to investigate novel biological and other markers.
17604367 Exacerbation of ulcerative colitis after rituximab salvage therapy. 2007 Nov BACKGROUND: B-cells are considered to play a pathogenic role in human ulcerative colitis (UC) by producing autoantibodies that cause epithelial cell damage. Here we report on a patient with intractable UC who suffered from a severe exacerbation of UC after salvage therapy with rituximab, a B-cell-depleting anti-CD20-antibody. METHODS: A 58-year-old patient with active long-standing UC and unresponsiveness or adverse events to mesalamine, corticosteroids, azathioprine, methotrexate, infliximab, leukapheresis, mycophenolate mofetil, and adalimumab received 375 mg/m(2) rituximab. RESULTS: A severe exacerbation of UC activity was noted upon therapy that required hospitalization. Subsequent studies showed a complete depletion of CD20-positive mucosal B-cells associated with a suppression of local IL-10 production. CONCLUSIONS: In contrast to rheumatoid arthritis patients, rituximab had deleterious effects in our UC patient by blocking IL-10 producing B-cells. Our data suggest an important anti- rather than proinflammatory role of B-cells in UC.
18725286 High-resolution melting curve analysis for genotyping of common SNP in MTHFR gene using fi 2008 Oct Genetic variation in MTHFR might explain the interindividual differences in both therapeutic and toxic responses to the treatment of cancer and rheumatoid arthritis with methotrexate, and can be involved in the sensitivity of developing diseases like cancer and congenital anomalies. We investigated the common sequence variation, C677T, in the MTHFR gene in fixed-cell specimens archived after chromosomal analysis using a novel gene scanning method based on post PCR analysis of high-resolution melting curves (HRM). These fixed specimens were stored after routine chromosomal analysis for 1 year at -20 degrees C in a 3:1 methanol:acetic acid solution. The method revealed a distinct pattern between homozygous and heterozygous alleles. Sensitivity and specificity of the HRM based method were comparable to that obtained by a hybridization probe. While the success rate for genotyping of a common SNP in MTHFR was similar to the hybridization probe approach, the HRM based method was more cost-effective and had a shorter turnaround time.
18068874 [Management of cytomegalovirus infections in patients treated with immunosuppressive drugs 2008 Apr INTRODUCTION: For patients with chronic inflammatory disease treated by immunosuppressive agents (for example: rheumatoid arthritis or systemic lupus erythematosus), there are no available guidelines in medical literature on the use of antiviral agents for the management of symptomatic cytomegalovirus (CMV) infection. EXEGESIS: A patient treated by methotrexate for a spondylarthritis presented a CMV infection manifested with persistent fever and pneumonia. CMV pp65 antigenemia was of 120 positive nuclei for 100,000 cells. Treatment with valganciclovir allowed a prompt recovery, while treatment by methotrexate was maintained. CONCLUSION: Symptomatic CMV infection evolution is unpredictable and potentially severe in patients with chronic inflammatory diseases receiving immunosuppressive agents. Although there is no data issued from clinical trials, the observation reported in this article and the publications of similar cases in the medical literature indicate that treatment with valganciclovir seems worth to be used in this context. Stopping immunosuppressive therapy does not seem mandatory.
19016697 Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms. 2009 Feb BACKGROUND: The use of methotrexate is limited by interindividual variability in response. Previous studies in patients with either rheumatoid arthritis or psoriasis suggest that genetic variation across the methotrexate metabolic pathway might enable prediction of both efficacy and toxicity of the drug. OBJECTIVES: To assess if single nucleotide polymorphisms (SNPs) across four genes that are relevant to methotrexate metabolism [folypolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC)] are related to treatment outcomes in patients with psoriasis. METHODS: DNA was collected from 374 patients with psoriasis who had been treated with methotrexate. Data were available on individual outcomes to therapy, namely efficacy and toxicity. Haplotype-tagging SNPs (r(2) > 0.8) for the four genes with a minor allele frequency of > 5% were selected from the HAPMAP phase II data. Genotyping was undertaken using the MassARRAY spectrometric method (Sequenom). RESULTS: There were no significant associations detected between clinical outcomes in patients with psoriasis treated with methotrexate and SNPs in the four genes investigated. CONCLUSIONS: Genetic variation in four key genes relevant to the intracellular metabolism of methotrexate does not appear to predict response to methotrexate therapy in patients with psoriasis.
17297594 Characteristics of patients with systemic lupus erythematosus (SLE) and non-Hodgkin's lymp 2007 Sep Patients with systemic lupus erythematosus (SLE) are at increased risk of developing non-Hodgkin's lymphoma (NHL), but features of SLE associated with NHL are not well described. The objective of this study was to describe SLE characteristics, laboratory serologies, and medication histories in patients who subsequently develop NHL. Two thousand twenty patients with SLE were identified using the online Partners' patient database research tool between October 1992 and June 2005. We confirmed the diagnoses of SLE and NHL and sought details of medical history and treatment by medical record review. Eleven patients with NHL without coexisting rheumatoid arthritis, Sjögren's, or HIV were identified; seven of these (64%) had a diffuse large B cell lymphoma subtype, and 83% of those stained were Epstein-Barr virus (EBV) negative. The mean duration of SLE at NHL diagnosis was 17.8 years (range 1.6-41.8), and the mean Systemic Lupus International Collaborative Clinics/American College of Rheumatology damage index was 1.9. Seven patients (64%) had SLE hematologic involvement, four had anti-dsDNA antibodies, and four had anti-phospholipid antibodies. One patient had significant renal disease. All patients had arthritis and had received antimalarial therapy. Five of 11 patients had received other treatments for SLE, including cyclophosphamide, imuran, methotrexate, and/or sulfasalazine. Diffuse large B cell lymphoma was the most common subtype of NHL, and most were EBV negative. Although disease duration was fairly long and end organ damage moderately severe in this group of patients, renal disease and the use of immunosuppressive chemotherapeutic agents were rare and did not appear to confer an increased risk of NHL development.
17596907 [Large granular lymphocyte leukemia]. 2007 Nov Large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic cells, either CD3(+) (T-cell) or CD3(-) (natural killer, or NK). Both subtypes can manifest as indolent or aggressive disorders. T-LGL leukemia is associated with cytopenias and autoimmune diseases and most often has an indolent course and good prognosis. Rheumatoid arthritis and Felty syndrome are frequent. NK-LGL leukemias can be more aggressive. LGL expansion is currently hypothesized to be a virus (Ebstein Barr or human T-cell leukemia viruses) antigen-driven T-cell response that involves disruption of apoptosis. The diagnosis of T-LGL is suggested by flow cytometry and confirmed by T-cell receptor gene rearrangement studies. Clonality is difficult to determine in NK-LGL but use of monoclonal antibodies specific for killer cell immunoglobulin-like receptor (KIR) has improved this process. Treatment is required when T-LGL leukemia is associated with recurrent infections secondary to chronic neutropenia. Long-lasting remission can be obtained with immunosuppressive treatments such as methotrexate, cyclophosphamide, and cyclosporine A. NK-LGL leukemias may be more aggressive and refractory to conventional therapy.
18762934 Limits of add-on trials: antirheumatic drugs. 2009 Jan PURPOSE: This paper assesses the design of clinical studies used in the process of regulatory approval, focusing on how add-on studies affect regulatory decisions. METHODS: The sample case taken is that of the new agents for rheumatoid arthritis (RA) authorised by the European Medicine Agency (EMEA). The European Public Assessment Reports (EPARs) accompanying the marketing authorisations were the source of information on the studies presented in the registration dossiers. RESULTS: The recently approved anti-RA agents are all indicated in combination with methotrexate (MTX) for treating adults with active RA who have responded inadequately to disease-modifier drugs (DMARDs). The add-on design was frequently used in registration studies. For infliximab, etanercept, adalimumab and rituximab, add-on trials contributed, together with parallel-group trials, to gaining the approval as combination therapy. Anakinra and abatacept were authorised on the basis of add-on trial results only. CONCLUSIONS: Add-on trials do not allow assessment of the intrinsic efficacy and safety of new agents and their value as alternatives to available treatments. The indications granted for the new anti-RA agents do not specify whether newer drugs can replace standard treatments in nonresponders, can do better in the overall patient population or can be used as first-line treatment.
16526326 Pancytopenia after low dose methotrexate therapy in a hemodialysis patient: case report an 2006 Methotrexate (MTX) is widely used in the treatment of rheumatoid arthritis (RA) with a side effect of pancytopenia. However, only a few cases of severe pancytopenia caused by low-dose MTX therapy have been reported, and the condition is rarely reported in uremic patients on dialysis therapy. We thereby report a hemodialysis patient who developed severe pancytopenia after oral treatment with low-dose MTX for RA. A 55-year-old woman who had been on regular hemodialysis treatment for 7 yr suffered from RA for 10 yr. She was regularly treated with celecoxib, prednisolone, and sulfasalazine in the past year. Because of the increasing arthralgia, 7.5 mg per week MTX was prescribed 3 months before admission. Stomatitis, fever, general fatigue, multiple skin carbuncles, and easy bruising developed after a cumulative dose of 90 mg. Pancytopenia was found at admission and the nadir of white blood cell count was 250/microL with 28% neutrophils, hematocrit was 22%, and platelet count was 6000/microL. Eosinophil counts increased from 11.5% initially to 26.1% on the sixth admission day. Transfusion with red blood cells and platelets, and appropriate antibiotics and folic acid were prescribed. She continued receiving regular hemodialysis and eventually recovered within 3 weeks.
17409534 Genetic polymorphism of C452T (T127I) in human gamma-glutamyl hydrolase in a Japanese popu 2007 Apr We investigated the genotype distribution and allele frequency of C452T polymorphism of gamma-glutamyl hydrolase (GGH) gene, which causes the decreased enzymatic activity affecting the efficacy of methotrexate (MTX), in a Japanese population. The polymerase chain reaction-restriction fragment length polymorphism assay was applied to determine the genotype of C452T polymorphism in 269 Japanese healthy individuals. The genotype distribution was as follows: C/C, 89.2% (n=240); C/T, 10.4% (n=28); T/T, 0.4% (n=1). The frequency of C and T allele was 0.944 and 0.056, respectively. The obtained genotype distribution was well agreed with those expected by Hardy-Weinberg equilibrium. The genotype distribution and allele frequency in a Japanese population were found to be similar to those of African-Americans but significantly different from Caucasians. Although the frequency of variant T allele in a Japanese population is not so high as compared to Caucasians, determination of C452T polymorphism of GGH may be useful for monitoring of efficacy and side-effects of MTX for treatment of diseases such as rheumatoid arthritis or childhood acute leukemia. To our knowledge, this is the first report about the examination of C452T polymorphism of GGH in a Japanese population.