Browse

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

ID PMID Title PublicationDate abstract
15464598 Efficient isolation of cDNA clones encoding rheumatoid arthritis autoantigens by lambda ph 2004 Oct 19 Bacteriophage lambda surface display was used to isolate cDNA clones encoding autoantigens recognized by synovial fluid (SF) or sera from patients with rheumatoid arthritis (RA). We constructed cDNA libraries from human synovial sarcoma cells and synovial tissue, using the surface display vector lambdafoo. The cDNA libraries were screened by affinity selection using 40 SF and 44 sera as probes separately immobilized in microtiter wells. Phage clones isolated encode 13 different autoantigens; an unknown protein, two proteins previously unanalyzed as autoimmune antigens, three proteins previously unknown to be recognized by RA sera, and seven known RA antigens. When analyzed their sensitivity and specificity for RA by phage enzyme-linked immunosorbent assay, frequencies of sera that recognize the newly-isolated autoantigens ranged from 20.5 to 6.8% of a panel of RA sera, and 13.6-0% of other autoimmune disease sera. These results indicate that the lambda phage surface display may be powerful for the isolation of cDNA clones encoding autoantigens recognized by SF or sera from patients with not only RA but also other autoimmune diseases.
12514522 [Bullous localization of a lupus erythematosus induced by radiotherapy]. 2002 Nov INTRODUCTION: Connective diseases induced or exacerbated by radiotherapy are not frequent. We report a particular erosive erythematosus lupus with lesions in the precise distribution of radiation therapy given for a breast cancer. OBSERVATION: An 80 year-old woman presented with painful erosive skin lesions of her breast which had been treated by irradiation 9 years before. The patient also had rheumatoid arthritis. A skin biopsy showed keratinocyte necrosis, acantholysis and a dermal lymphocytic infiltrate under the basal cell layer. Direct immunofluorescence showed granular deposition of IgG, IgM and C3 along the basal cell layer. Antinuclear antibodies were positive at a titre of 1: 1,000. Erythematosus lupus diagnosis was established and annular lesions secondarily appeared on her neck, back, and arms. A treatment with hydroxychloroquine and topical corticosteroïds was effective in 3 months. DISCUSSION: The unusual erosive lesions and their localization on a previously irradiated site suggest the role of X-rays in our observation, despite their late appearance after radiotherapy. Radiotherapy and erythematosus lupus affect the same target structures (basal cells and small dermal capillaries) and could have additive effects. The presence of rheumatoid arthritis in the past medical history may have exaggerated this complication.
11950127 Improved medication use in long-term care: building on the consultant pharmacist's drug re 2002 Apr Elderly and long-term care (LTC) patients often require complex medication regimens that increase their risk of adverse drug events or suboptimal pharmacotherapy. Currently, oversight of medication use in LTC facilities consists of a federally mandated monthly audit, the drug regimen review (DRR), performed by a consultant pharmacist, and yearly onsite government surveys. Although the DRR's purpose is to improve drug use and to avoid adverse drug events, the Centers for Medicare and Medicaid Services's (CMS) current DRR guidelines focus on a limited selection of medications and indications rather than on patient outcomes. An expanded model building on CMS's survey guidelines and the American Society of Consultant Pharmacists' Fleetwood Model is proposed to improve oversight of medication use. The proposed model includes using consultant pharmacists with demonstrated geriatric pharmacotherapy expertise, direct patient assessments by the pharmacist, increased interaction among healthcare professionals, evidence-based practices, and explicit patient outcome assessments. It is both feasible and timely: (1) the LTC prospective payment system aligns financial incentives between payers and providers; and (2) the Institute of Medicine has made quality improvement and error reduction a priority.
15126674 Rheumatoid vasculitis: becoming extinct? 2004 Jul BACKGROUND: Systemic rheumatoid vasculitis (SRV) is a relatively rare complication of RA. The incidence of SRV appeared to increase during the 1970s and 1980s from 6.0 to 12.5/million. During the 1990s there have been major changes in the treatment of RA, with more aggressive control of inflammation. Our aim was to study the epidemiology of SRV in a stable, well-defined population over a 15-yr period. METHODS: Since 1988 we have maintained a prospective register of all patients with systemic vasculitis attending the Norfolk and Norwich University Hospital. Patients presenting with new-onset SRV, as defined by the criteria of Scott and Bacon, and registered with general practitioners in the former Norwich Health Authority area between 1988 and 2002 were identified. The population in 2002 was estimated to be 445 000 (215 000 males). RESULTS: Fifty-one patients (24 male) with SRV were identified, with median age 61 yr and disease duration 16.8 yr. The overall annual incidence was 7.9/million (95% CI 5.9-10.4) (males, 7.7/million; females, 8.1/million). During the first quinquennium (1988-92) the incidence was 11.6/million (95% CI 7.4-17.0) and during the third (1998-2002) it was 3.6/million (95% CI 1.6-7.1). A rolling 3-yr average showed that the peak incidence was in 1992-94, at 15.2/million (95% CI 9.1-23.8), and the nadir was in 1998-2000, at 3.0/million (95% CI 0.8-7.8). A similar pattern was seen for males and females. There was no difference in age or disease duration at onset of SRV between the three quinquennia. CONCLUSIONS: The incidence of SRV has declined dramatically since the 1980s. This could be due to better control of inflammatory disease or changes in smoking habits.
12482190 HLA-DRB1 genes and susceptibility to rheumatoid arthritis in three ethnic groups from Mala 2002 Jul Worldwide population studies have generally agreed that rheumatoid arthritis (RA) is associated with a group of HLA-DRB1 alleles which share a common amino acid sequence at residues 70-74. This represents the first study to investigate the association of HLA-DRB1 genes with susceptibility to RA amongst Malay, Chinese and Indian ethnic groups in Malaysia. One hundred and thirty three RA patients and one hundred and sixty seven healthy controls were recruited. The HLA-DRB1 alleles were studied using the Phototyping method. The subtypes of HLA-DR4 were detected by "high resolution" PCR-SSP DRB1*04 typing techniques. The prevalence of HLA-DRB1*0405 was significantly higher in Malay patients with RA than in healthy controls (28.9 vs. 8.3%, p = 0.0016, OR = 4.48, 95% CI = 1.26-16.69). Similarly, DRB1*0405 was more common in Chinese RA patients than in controls (30.0 vs. 6.7%, p = 0.0029, OR = 6.00, 95% CI = 1.67-23.48). In addition, DRB1*0901 was a predisposing factor (32.0 vs. 6.7%,p = 0.0015, OR = 6.59, 95% CI = 1.85-25.64) and *0301/04 had a protective role (4.0vs. 25.0%, p = 0.00562, OR = 0.13, 95% CI = 0.02-0.62) in Malaysian Chinese RA. RA in Indians was associated with DRB1*1001 (51.1 vs. 8.5%,p = 0.00002, OR = 11.24, 95% CI = 3.13-44.18). DRB1*0701 (13.3 vs. 42.6%,p = 0.0022, OR = 2.73, 95% CI = 1.40-5.37) may have a protective effect. Therefore, in the Malaysian population, RA is primarily associated with the QRRAA motif, and we suggest that genetic factors play a crucial role in the pathogenesis of RA, compared to environmental factors.
12833393 Simultaneous determination of leflunomide and its active metabolite, A77 1726, in human pl 2003 Jun The isoxazol derivative leflunomide [N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide] is an inhibitor of de novo pyrimidine synthesis used for the treatment of rheumatoid artrithis. In the present study, a liquid-liquid extraction-based reversed-phase HPLC method with UV detection was validated and applied for the analysis of leflunomide and its active metabolite, A77 1726, in human plasma. The analytes were separated using a mobile phase, consisting of acetonitrile, water and formic acid (40/59.8/0.2, v/v), at a flow rate of 0.5 mL/min, and UV detection at 261 nm. The retention times for A77 1726, leflunomide and warfarin (internal standard) were 8.2, 16.2 and 12.2 min, respectively. The validated quantification range of the method was 0.05-100 micro g/mL for leflunomide and 0.1-100 micro g/mL for A77 1726. The developed procedure was applied to assess steady-state plasma concentrations of A77 1726 in patients with rheumatoid arthritis treated with 10 or 20 mg leflunomide per day.
14515143 Interleukin-6 biology is coordinated by membrane bound and soluble receptors. 2003 Cytokine receptors exist in membrane bound and soluble form. Both forms bind their ligands with comparable affinity. While most soluble receptors are antagonists in that they compete for the ligands with their membrane counterparts, some soluble receptors are agonists. In this case, the complex of ligand and soluble receptor binds on target cells to a second receptor subunit and initiates signal transduction. Soluble receptors of the IL-6 family of cytokines are agonists. In vivo, the IL-6/soluble IL-6R complex stimulates several types of target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. This process has been named transsignaling. We have shown that in several chronic inflammatory diseases like chronic inflammatory bowl disease, peritonitis and rheumatoid arthritis, transsignaling via the soluble IL-6R complexed to IL-6 is a crucial point in the transition from the acute to the chronic state of the disease. The mechanism by which the IL-6/ soluble IL-6R complex regulates the inflammatory state is discussed.
11981603 Quantitative ultrasound in the assessment of bone status of patients suffering from rheuma 2002 May OBJECTIVE: To explore the effects of rheumatic diseases and glucocorticoids on bone mass a group of patients suffering from systemic lupus erythematosus (SLE, n=18) and rheumatoid arthritis (RA, n=22) were examined. DESIGN: We examined 40 patients and 48 controls with quantitative ultrasound (QUS) and dual-energy X-ray absorptiometry (DXA). RESULTS: QUS (broadband ultrasound attenuation, BUA; speed of sound, SOS) values were found to be significantly lower in patients than in controls ( P<0.001). QUS measurements were moderately correlated with DXA measurements (kappa score ( kappa) 0.28 at the lumbar spine, and 0.46 at the femoral neck). There were no significant relations between the dosage of glucocorticoids and QUS parameters. CONCLUSION: In patients suffering from inflammatory rheumatic diseases QUS values were significantly decreased. SOS but not BUA and DXA measurements reflected disease activity assessed by erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). QUS reflects different aspects of bone status compared with DXA.
12117685 Expression of ferritin, transferrin receptor, and non-specific resistance associated macro 2002 Aug OBJECTIVE: To gain a better understanding of how iron accumulates in human rheumatoid synovium. METHODS: The distribution of ferritin, transferrin receptor, and non-specific resistance associated macrophage proteins 1 and 2 (Nramp1 and Nramp2) in the human rheumatoid synovium was investigated by immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: Both heavy and light ferritin subunit types were detected in the lining layer and the subinitimal zone of rheumatoid synovium, heavy ferritin generally being more abundant than light. Both heavy and light ferritin were detected in isolated synovial macrophages and fibroblasts. Transferrin receptor expression was largely confined to fibroblasts of the synovial lining layer. Nramp2 was detected by PCR in both isolated synovial macrophages and fibroblasts, whereas Nramp1 was detected by PCR and immunocytochemistry in macrophages and neutrophils in the lining and subinitimal zone, and in inflammatory infiltrates, but was absent from fibroblasts. CONCLUSION: A complex chain of events, perhaps initiated by proinflammatory cytokines, may culminate in a toxic build up of iron in the rheumatoid joint.
15546339 Cytotoxic T-lymphocyte antigen-4-CT60 polymorphism in rheumatoid arthritis. 2004 Dec Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a functional candidate gene with susceptibility to rheumatoid arthritis (RA). The aim of this work was to investigate the possible influence of the recently described CT60A/G dimorphism of the CTLA-4 gene in the susceptibility to RA in Spanish patients. A total of 433 RA patients and 398 control subjects were included in the study. Genotyping of CTLA-4 CT60 was performed using two different methods: polymerase chain reaction restriction fragment length polymorphism system using an amplification-created restriction site and a TaqMan 5'-allelic discrimination assay. In order to validate results obtained by different methods, a quality-control exercise was performed. No significant deviation in the distribution of the alleles or genotypes of the CT60 was found when we compared RA patient and control groups. In addition, no differences in CTLA-4 CT60 genotypic distribution was found when RA patients and controls were stratified by the presence or absence of the shared epitope. In conclusion, our results do not support an association between CT60A/G polymorphism and susceptibility to RA in the Spanish population, although the contribution of other positions located within the 3' region of the CTLA-4 gene to RA susceptibility cannot be discarded.
15027313 [Clinical significance of serum IL-18 determination in rheumatoid arthritis]. 2004 Feb Interleukin (IL)-18 is a novel cytokine expressing at inflammatory lesion. In this study, to evaluate the clinical significance of IL-18 determination, we have examined serum IL-18, inflammation markers, sFas, and sFas-ligand concentrations in patients with rheumatoid arthritis(RA). Serum was obtained from 56 RA patients aged 35-74 years, 16 osteoarthritis (OA) patients aged 36-78 years and 178 healthy subjects aged 20-72 years and IL-18 was measured by ELISA. Serum IL-18 concentrations in RA (240.1 +/- 15.6 pg/ml, mean +/- SE) were significantly higher than OA (151.8 +/- 12.7 pg/ml, p < 0.005) and healthy controls(141.5 +/- 26.1 pg/ml, p < 0.001). Serum IL-18 levels were significantly increased in II to IV stages of RA (stage II; 218.6 +/- 31.2 pg/ml, stage III; 258.7 +/- 38.4 pg/ml, stage IV; 231.6 +/- 13.1 pg/ml) than those in OA. Furthermore, a positive correlation was observed between serum IL-18 concentration and serum Fas level in patients with RA (r = 0.472), whereas there was no significant correlation between serum IL-18 and sFas-ligand or other inflammatory markers (CRP, RF, CA-RF, IL-6, and IL-8). The present study showed that serum IL-18 level increased in RA, but it is unknown how IL-18 is involved in the pathogenesis of RA. Further study will be necessary to clarify the role of IL-18 in RA.
15571587 Outcome of pregnancy in women receiving infliximab for the treatment of Crohn's disease an 2004 Dec OBJECTIVES: Infliximab is approved for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). We report the first large series of pregnancy outcomes in women with RA and CD exposed to infliximab. METHODS: The infliximab safety database was queried for all reports of pregnancy. Data were extracted regarding the indication for infliximab, timing of infliximab relative to conception, pregnancy course, and pregnancy outcome. The proportion of live births, miscarriages, and therapeutic terminations for women directly exposed to infliximab before or during confirmed pregnancy were compared to those expected for the general U.S. population of pregnant women and pregnant women with CD not exposed to infliximab. RESULTS: Of the 146 identified pregnancies, 131 involved women exposed directly to infliximab and outcome data were available for 96 of these women. Live births occurred in 67% (64/96), miscarriages in 15% (14/96), and therapeutic termination in 19% (18/96) of the pregnancies directly exposed to infliximab with available outcome data. These results are similar to those expected for the general U.S. population of pregnant women or pregnant women with CD not exposed to infliximab. CONCLUSION: Data from the infliximab safety database suggest that infliximab exposure during pregnancy results in outcomes that do not differ from those in the U.S. population of pregnant women and pregnant women with CD not exposed to infliximab. No increased risk of adverse outcome was detected, however, follow-up of larger numbers of pregnant women exposed to infliximab will be necessary to definitively exclude any fetal risk.
12602968 Cutaneous infection due to Scedosporium apiospermum in an immunosuppressed patient. 2003 Jan Scedosporium apiospermum, the anamorphic form of Pseudallescheria boydii, is a filamentous fungus with low inherent virulence. Increasing numbers of cases of this infection have been reported probably related to the rising number of immunosuppressed persons. Apart from mycetoma, cutaneous and subcutaneous infection is rarely encountered in clinical practice. We describe a case of cutaneous infection caused by Scedosporium apiospermum in a subject with rheumatoid arthritis and diabetes mellitus who was submitted to long-term therapy with cyclosporin and corticosteroids. Histopathologic examination of a skin biopsy showed a granulomatous infiltrate with hyaline septate hyphae. Culture of two skin biopsies taken at two different observations of the woman, 3 weeks apart, allowed isolation of Scedosporium apiospermum. Therapy with itraconazole, 400 mg/day, for 3 months was effective in curing the infection.
14649677 The combination of systemic antibiotics and antibiotics impregnated cement in primary tota 2003 Sep BACKGROUND: We evaluated the effect of combination of systemic antibiotics and antibiotics-impregnated cement in prevention of deep infection in primary total knee arthroplasty (TKA) in patients of rheumatoid arthritis (RA). METHODS: Between 1993-2000, primary TKA were performed for 60 RA patients. Systemic antibiotics with cefazolin and gentamycin were applied in all the patients. Cefuroxime-impregnated cement was used for fixation of tibial and patellar components in all the patients; femoral component was fixed noncementedly in 45 patients (hybrid TKA) and cementedly in 15 patients (cemented TKA). The preoperative, intraoperative and postoperative courses were evaluated in detail. The mean follow-up period was 61 months (range: 24-108 months). The effect of cefuroxime-impregnated cement in the prevention of postoperative deep infection in primary TKA in cases of RA was evaluated. RESULTS: Except 1 (1.6%) superficial infection, no other complication was noted. There was no deep infection, either. CONCLUSIONS: Cefuroxime-impregnated cement combining with systemic antibiotics seems to be effective in the prevention of early or intermediate deep infection in primary TKA in patients of RA.
15345499 Galectin-3 is induced in rheumatoid arthritis synovial fibroblasts after adhesion to carti 2005 Mar BACKGROUND: Galectin-3 is expressed in the synovial tissue of patients with rheumatoid arthritis (RA), particularly at sites of joint destruction. OBJECTIVE: To explore the possibilities that galectin-3 is induced either by proinflammatory cytokines or by adhesion to cartilage components. METHODS: Cell culture plates were coated with fibronectin, collagens I-VI, or cartilage oligomeric matrix protein (COMP), and the suspended cells were then added. The medium was changed after 1 hour at 37 degrees C. Adherent cells were further incubated for 18 hours in the presence or absence of tumour necrosis factor alpha (TNF alpha) or interleukin 1 beta. Cells were pretreated with murine IgG1, anti-CD29, -CD51, -CD61 (integrins), or -CD3 monoclonal antibodies and transferred to culture plates coated with COMP. Adherent cells were counted by light microscopy. The expression of intracellular galectin-3, or cell surface CD29, CD51, and CD61 was determined by flow cytometry before and after adhesion. RESULTS: Four times more RA synovial fibroblasts (SF) than osteoarthritis SF adhered to COMP. RA SF presented more cell surface integrins, and monoclonal antibodies against CD51 inhibited the adhesion to COMP by 80%. TNF alpha reduced the expression of CD61 and the adhesion to COMP, but did not reverse the adhesion once it had taken place. The adhesion of RA SF to COMP was found to increase the intracellular level of galectin-3. In contrast, intracellular galectin-3 decreased after exposure to TNF alpha. CONCLUSION: The increase of galectin-3 occurs after adhesion to COMP, and the alpha V beta 3 receptor (CD51/CD61) has a pivotal role in this process.
14561908 Methotrexate-induced pulmonary injury: serial CT findings. 2003 Oct We describe serial computed tomographic (CT) findings of methotrexate (MTX)-induced pulmonary injury. MATERIALS AND METHODS: The cases of 8 patients (3 men and 5 women; mean age 58.6 years, range 16 to 75 years) of clinically diagnosed MTX-induced pulmonary injury were reviewed. Six patients had rheumatoid arthritis, 1 had lupus erythematosus profundus, and 1 had juvenile rheumatoid arthritis. CT findings on admission and at follow-up were evaluated. RESULTS: The most common CT features were diffuse and patchy bilateral ground-glass opacity with (n = 3) or without reticulation (n = 4) and consolidation (n = 1). These opacities showed no predilection for any particular lung zone in 6 patients but did show dependent predilection in 1 patient and upper lobe predilection in 1. Diffuse centrilobular ill-defined nodules were noted in 1 patient, which disappeared on follow-up. During the average post-treatment follow-up period of 31.0 days (range 3 to 76 days), the opacities quickly improved after treatment in 6 patients; however, in 2 patients with pre-existing interstitial pneumonitis the opacities were refractory. CONCLUSION: CT features of MTX-induced pulmonary injury were variable and included diffuse parenchymal opacification, reticular opacities, and centrilobular nodules. These opacities usually responded quickly to treatment; however, those patients with lung fibrosis at presentation may have worse prognosis.
14513800 [Effect of lipopolysaccharide on expression of interleukin-6 in human synoviocyte from pat 2003 Jun AIM: To study the effects of lipopolysaccharide (LPS), the supernatant of U937 cells stimulated with LPS and dexamethasone on interleukin-6 (IL-6) expression in the synoviocyte from patients with rheumatoid arthritis (RA). METHODS: Fibroblast-like synoviocytes (FLS) from the joint tissue of patients with rheumatoid arthritis were cultured and incubated for 24 h with LPS (1 mg.L-1) or the supernatant of U937 cells stimulated with LPS (1 mg.L-1) for 24 h. Dexamethasone was added to the supernatant of U937 cells and FLS was incubated for 24 h. The expression of IL-6 protein was detected by radioimmunoassay. The mRNA expression of IL-6 was accessed by RT-PCR. RESULTS: The growth of FLS was not markedly affected by LPS, and the protein secretion and mRNA expression of IL-6 were not markedly changed in FLS treated with LPS. The IL-6 secretion and IL-6 mRNA expression were significantly increased in FLS cultured with the supernatant from U937 cell treated with LPS. Dexamethasone markedly inhibited the protein secretion and mRNA expression of IL-6 in FLS cultured with the supernatant from U937 cell stimulated with LPS. The inhibitory effects were increased as the concentration of dexamethasone increased. CONCLUSION: LPS was not shown to directly affect the expression of IL-6 in FLS, but it indirectly causes the increase of the IL-6 expression in FLS by stimulating U937 cell. Dexamethasone can inhibit this increase of the IL-6 expression.
12396472 Blood serotonin and joint pain in seropositive versus seronegative rheumatoid arthritis. 2002 Aug AIM: To investigate whether blood serotonin (5-hydroxytryptamine) (5-HT) modulates musculoskeletal pain differently in seropositive and seronegative rheumatoid arthritis (RA). METHODS: Patients with temporomandibular joint (TMJ) involvement of seropositive RA (33 patients) or seronegative RA (28 patients) and 26 healthy individuals were included. TMJ pain, general musculoskeletal pain, plasma and serum 5-HT, acute phase reactants and thrombocyte count were investigated. RESULTS: The patients with seropositive RA had higher serum (median = 1130 nmol/l) and plasma (55 nmol/l) levels of 5-HT than the healthy individuals (704 nmol/l, p = 0.044 and 23 nmol/l, p < 0.001, respectively), and higher plasma levels of 5-HT than the seronegative patients (14 nmol/l, p < 0.001). There was no significant correlation between serum and plasma levels of 5-HT in any group. In the seropositive RA patients, positive correlations were found between serum levels of 5-HT and the number of painful mandibular movements (r(s) = 0.36, n = 33, p = 0.042), as well as pain on maximum mouth opening (r(s) = 0.41, n = 24, p = 0.047) and tenderness to digital palpation (r(s) = 0.49, n = 33, p = 0.003). In the healthy individuals, there was a negative correlation between plasma level of 5-HT and the TMJ pressure pain threshold (r(s) = -0.47, n = 20, p = 0.037). CONCLUSION: Peripheral serotonergic pain mechanisms seem to be activated by blood 5-HT in patients with seropositive RA, in contrast to seronegative patients.
15457444 Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, amino 2004 Sep OBJECTIVE: Methotrexate (MTX) enters cells through the reduced folate carrier (RFC-1) and exerts part of its effects through polyglutamation to MTX polyglutamates (MTXPGs) and inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) and thymidylate synthase (TS). We investigated the contribution of common genetic polymorphisms in RFC-1 (G80A), ATIC (C347G), and TS (28-bp tandem repeats located in the TS enhancer region [TSER*2/*3]) and of MTXPGs to the effect of MTX in patients with rheumatoid arthritis. METHODS: The study was cross-sectional. All patients received MTX for at least 3 months. The numbers of tender and swollen joints, the Visual Analog Scale (VAS) scores for the physician's global assessment of disease activity, and the modified Health Assessment Questionnaire scores were collected. Using the VAS score for the physician's assessment of patient's response to MTX, the population of patients was dichotomized into responders to MTX (VAS score < or =2 cm) and nonresponders to MTX (VAS score >2 cm). A pharmacogenetic index was calculated as the sum of homozygous variant genotypes (RFC-1 AA + ATIC 347GG + TSER *2/*2) carried by the patients. MTXPG concentrations were measured in red blood cells (RBCs) by high-performance liquid chromatography. RESULTS: The dose of MTX was not associated with the effects of MTX (P > 0.05). In contrast, increased RBC long-chain MTXPG concentrations (median 40 nmoles/liter; range <5-131 nmoles/liter) and an increased pharmacogenetic index were associated with a lower number of tender and swollen joints (P < 0.05) and a lower score for the physician's global assessment of disease activity (P < or = 0.001). Patients with RBC MTXPG levels of >60 nmoles/liter and carriers of a homozygous variant genotype were 14.0-fold (95% confidence interval [95% CI] 3.6-53.8) and 3.7-fold (95% CI 1.7-9.1), respectively, more likely to have a good response to MTX (P
12610315 Methotrexate: first-line or second-line immunomodulator? 2003 Mar Methotrexate is established as an effective treatment for inducing remission or preventing relapse in Crohn's disease. This review discusses the mechanisms of action, pharmacokinetics and clinical trials as well as considering the comparative efficacy between thiopurines and methotrexate. Comparisons are made with the treatment of rheumatoid arthritis. Its role in ulcerative colitis and potential toxicity are addressed. At present, the role of methotrexate is in the treatment of active or relapsing Crohn's disease for patients who are refractory to, or intolerant of, azathioprine or 6-mercaptopurine.