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PMID	Title	PublicationDate	abstract
12846051	Treatment of early RA in clinical practice: a comparative study of two different DMARD/cor	2003 May	OBJECTIVES: To study the outcome in clinical practice of first DMARD and/or corticosteroid (CS) treatment in patients with recent onset rheumatoid arthritis (RA). PATIENTS: 245 patients with active RA, not previously treated with DMARDs or CS, were randomised to one of two treatment groups, T1 = 7.5-15 mg of prednisolone (PRE) daily for one to three months followed, if needed, by methotrexate (MTX) in a weekly dose of 5-15 mg in addition to the lowest possible dose of PRE or T2 = sulfasalazine (SAL), supplemented with lowest possible CS dose if needed. METHODS: The EULAR individual response criteria were applied and remission was defined as a final DAS28 < 2.6. Function was assessed by the HAQ and radiographic progression by Larsen scores. A patient who managed to remain on the allocated treatment for two years was described as a "completer". RESULTS: After 2 years of treatment, 70% of the patients in T1 and 63% in T2 were responders (30% and 33% "good responders", respectively). In T1 29% and in T2 19% were in remission. There was a significant functional improvement in both groups but radiographic progression occurred. The mean decrease in HAQ and increase in the Larsen score were similar in the two groups. One-third of the patients were non-completers, 19% from T1 and 47% from T2. Non-completers had, compared with completers, a significantly lower rate of individual response and remission. Completers and non-completers had similar functional improvement and similar radiological progression. CONCLUSIONS: Individual response and remission was reduced in patients who did not complete their first DMARD/CS treatment option. Treatment failures were significantly more frequent in the sulfasalazine plus optional CS than in the CS plus optional methotrexate treatment group.
12209503	Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessful	2002 Aug	OBJECTIVE: To assess the efficacy, safety, and optimal dose of tacrolimus monotherapy in patients with rheumatoid arthritis (RA). METHODS: This phase II, randomized, double-blind, placebo-controlled monotherapy study was set in 12 community sites and 9 university-based sites. Two hundred sixty-eight patients with RA who were resistant to or intolerant of methotrexate (mean dose 15.2 mg/week) and had active disease for at least 6 months (mean tender joint count 28.2, mean erythrocyte sedimentation rate 46.5 mm/hour) were randomized to receive treatment after discontinuation of methotrexate. Those who received at least 1 dose of tacrolimus were analyzed; 141 completed the study. Stable dosages of nonsteroidal antiinflammatory drugs and low-dose prednisone were allowed during treatment. All patients were given 1, 3, or 5 mg of tacrolimus or placebo once daily for 24 weeks. The American College of Rheumatology definition of 20% improvement (ACR20) and the tender and swollen joint counts at the end of treatment were the primary outcomes. RESULTS: ACR20 response rates demonstrated a clear dose response. The ACR20 response was observed in 15.5% of patients receiving placebo (95% confidence interval [95% CI] 7.1-23.9%), 29% of the 1 mg tacrolimus group (95% CI 18.3-39.7%) (P < 0.058); 34.4% of the 3 mg group (95% CI 22.7-46.0%) (P < 0.013), and 50% of the 5 mg group (95% CI 37.8-62.3%) (P < or = 0.001). The tender joint count improved statistically significantly in all tacrolimus groups. The swollen joint count, physical function, and patient-assessed pain improved statistically significantly in the 3 mg and 5 mg groups. The incidence of creatinine elevation > or =40% above baseline levels increased in a dose-dependent manner. Dropout rates were high (41-59%) and were more common for inefficacy in the placebo patients (71.4%), whereas they were more common for toxicity in the high-dose tacrolimus groups (31-33%). Discontinuation for creatinine elevation occurred in the 3 mg (3.1%) and 5 mg (10.9%) tacrolimus groups. CONCLUSION: Tacrolimus improved disease activity in methotrexate-resistant or -intolerant patients with RA. A dose response was observed when efficacy and toxicity were assessed at different doses. The optimal dose of tacrolimus appears to be >1 mg but < or=3 mg daily.
15457442	The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to	2004 Sep	OBJECTIVE: To examine the roles of specific genetic polymorphisms as predictors of response to treatment of early rheumatoid arthritis (RA). METHODS: Subjects included 457 patients with early RA (duration of < or =3 years) who participated in a randomized controlled trial comparing weekly methotrexate and 2 dosages of etanercept (10 mg twice weekly and 25 mg twice weekly). Our primary outcome measure was achievement of 50% improvement in disease activity according to the criteria of the American College of Rheumatology (ACR50 response) after 12 months of treatment. Subjects were genotyped for HLA-DRB1 alleles and polymorphisms in the following genes: TNF, LTA, TNFRSF1A, TNFRSF1B, FCGR2A, FCGR3A, and FCGR3B. Univariate and multivariate analyses were performed to define the impact of specific polymorphisms and haplotypes on response to treatment. Covariates for the multivariate analyses included sex, ethnicity, age, disease duration, and baseline values for rheumatoid factor and the tender and swollen joint counts. RESULTS: The presence of 2 HLA-DRB1 alleles encoding the shared epitope (SE) (compared with 1 or 0 copies) was associated with response to treatment with standard-dose etanercept (odds ratio [OR] 4.3, 95% confidence interval [95% CI] 1.8-10.3). Among Caucasian patients, 2 extended haplotypes that included the HLA-DRB1 alleles 0404 and 0101 (both of which encode the SE) and 6 single-nucleotide polymorphisms in the LTA-TNF region were associated with response to treatment. In a multivariate model that included treatment received and the aforementioned covariates, the ORs for the association of these haplotypes with achievement of an ACR50 response at 12 months were 2.5 (95% CI 0.8-7.3) and 4.9 (95% CI 1.5-16.1) for the 0404- and 0101-containing haplotypes, respectively. CONCLUSION: Genetic variation in the HLA-DRB1 and the LTA-TNF regions is significantly associated with response to treatment of early RA. These findings may have clinical application through the identification of patients who are most likely to benefit from treatment with methotrexate or etanercept.
11858354	Second-line drugs used in recent-onset rheumatoid arthritis in Brittany (France).	2002 Jan	OBJECTIVE: The management of recent-onset rheumatoid arthritis (RA) is not well standardized. We conducted a survey of drugs prescribed to RA patients in Brittany at presentation and during the first 1 to 3 years of follow-up. METHODS: A cohort of 270 patients with recent-onset inflammatory joint disease was recruited between 1995 and 1997. The evaluation at presentation included a medical history, a thorough physical examination, and a standard battery of investigations. Follow-up at 6-month intervals was offered. At the last visit, between June and December 1999, a panel of five rheumatologists established that 98 patients had RA. RESULTS: At presentation, hydroxychloroquine and injectable gold were the most widely used second-line drugs, and only two patients were offered a combination of second-line drugs. At the last visit, the most commonly used drugs were methotrexate, injectable gold, and hydroxychloroquine (23, 23, and 21 patients, respectively); only three patients were on more than one second-line drug and 38 (38/98, 39%) patients were on glucocorticoid therapy. CONCLUSION: Rheumatologists in Brittany prefer monotherapy with hydroxychloroquine or injectable gold as the initial treatment. Later, they rely mainly on methotrexate, injectable gold, and hydroxychloroquine, often in combination with glucocorticoid therapy.
12923291	A survey of British rheumatologists' DMARD preferences for rheumatoid arthritis.	2004 Feb	OBJECTIVE: To determine the current disease-modifying anti-rheumatic drug (DMARD) preferences of UK consultant rheumatologists. METHODS: A questionnaire was sent in May 2002. We asked which DMARD(s) was most frequently preferred first and sought the most typical sequence of DMARDs, including DMARD combinations. Also we determined the extent to which prognostic and other factors influenced treatment choices. Comments were invited, written responses abstracted and key themes identified. RESULTS: After two mailings, 331 (of 460; 72%) suitable questionnaires were returned. Ninety-five per cent (315/331) preferred methotrexate (154, 46.5%) or sulphasalazine (144, 43.5%) or either of these two (17, 5%) as first-choice agent. Of those who chose methotrexate first, 80% (123/154) ranked sulphasalazine second, 45% (55/123) combined sulphasalazine and methotrexate and 49% (27/55) then added hydroxychloroquine to this combination, in active disease. Of those who chose sulphasalazine first, 95% (137/144) ranked methotrexate second, 75% (113/150) preferring methotrexate monotherapy and 12% (18/150) the combination with sulphasalazine. Rheumatologists who preferred sulphasalazine first more commonly used subsequent DMARDs singly than those who started with methotrexate (P < 0.0001). Leflunomide was more commonly preferred than intramuscular gold as third choice (52/145 vs 29/145; P < 0.003). The most popular sequence of DMARDs was methotrexate or sulphasalazine, singly or in combination, leflunomide, intramuscular gold and anti-tumour necrosis factor therapy. Poor prognostic factors influenced DMARD choice, but patient occupation and drug costs did not. CONCLUSION: Methotrexate has displaced other DMARDs, especially sulphasalazine, as agent of first choice and newer agents have displaced older DMARDs. Whether the expressed preference for particular DMARDs accurately reflects actual use, and is optimal in rheumatoid arthritis, remains to be determined.
11974902	[Two fatal cases of methotrexate-induced interstitial pneumonitis].	2002 Mar	We report two cases of methotrexate-induced pneumonitis. Both patients died despite steroid pulse therapy. Postmortem lung tissue revealed diffuse alveolar damage, and focal lung fibrosis. Physicians should be aware of the possibility of MTX-induced interstitial pneumonitis in diagnosing RA patients with MTX when diffuse pulmonary infiltration is present.
12421102	Diagnosis and management of psoriatic arthritis.	2002	Psoriatic arthritis (PsA) is considered to be one of the spondyloarthritides, and as such has both spinal and peripheral joint involvement. In 80% of patients, psoriasis usually precedes the development of arthritis. Although there are no widely accepted diagnostic criteria, a number of distinct clinical features allow it to be distinguished from other forms of inflammatory arthritis. It affects both sexes equally, and the pattern of joint involvement is characteristic with distal interphalangeal joint involvement, asymmetry, dactylitis, flail or ankylotic deformities of digits, and the frequent presence of enthesitis and spinal involvement. It may have a pattern of joint involvement similar to rheumatoid arthritis (RA) but in these patients rheumatoid factor and the other systemic features of RA are usually absent. Radiographs frequently reveal evidence of asymmetric sacroiliitis and spinal disease, and peripheral joints, as well as showing erosions, may also demonstrate profuse new bone formation and ankylosis. Profound osteolysis producing the pencil-in-cup deformity can also occur in the same individual. It is now recognised that PsA can be a destructive arthritis with an increased morbidity and mortality. Studies of standard disease-modifying therapies have been small and frequently inconclusive because of a high placebo response rate. This may be as a result of heterogeneity in patient selection, poor assessment tools, or the difference in underlying pathogenesis and subsequent response to therapy. In meta-analyses, sulfasalazine and methotrexate have been shown to be effective. Treating the skin alone seems to have little impact on joint disease, and the relationship between skin and joints is still unclear. However, recent studies with anti-tumour necrosis factor agents, such as etanercept and infliximab, have shown considerable significant clinical benefit and provided the hope that we will at last have effective therapies for this disease.
15268666	Anakinra: an inhibitor of IL-1 for the treatment of rheumatoid arthritis.	2004 Aug	Anakinra (Amgen, Inc.) is a specific receptor antagonist of IL-1 that differs from naturally occurring IL-1 receptor antagonist by the presence of a methionine group. Anakinra has been shown to be of benefit in patients with active rheumatoid arthritis, either when given alone or in combination with methotrexate, as assessed by improvement in clinical signs and symptoms, decreased radiographic progression and improvement in patient function, pain and fatigue, although it appears to be effective in fewer patients than anti-TNF agents. It has a favourable safety profile as demonstrated in clinical trials. The physician and patient must be cognizant of serious infectious episodes. Many of the rare side effects seen with TNF blockers, such as tuberculosis, other opportunistic infections, worsening of congestive heart failure and the development of demyelinating disease, have not been seen in patients treated with anakinra. Anakinra should not be given in combination with anti-TNF agents.
15638051	Induction of autoantibodies in refractory rheumatoid arthritis treated by infliximab.	2004 Nov	OBJECTIVES: To investigate autoantibody induction in rheumatoid arthritis (RA) patients treated with infliximab. METHODS: We included 59 refractory RA patients treated with infliximab in combination with low-dose prednisone and methotrexate or leflunomide. We tested the sera of the patients for antinuclear antibodies (ANA), rheumatoid factor (RF), anti double-stranded DNA antibodies (anti dsDNA), anti-histone and anti-extractable nuclear antigen antibodies (aENA) at baseline and before infusion at weeks 6 and 30. Infliximab, initiated at a dose of 3 mg/kg, was increased to 5 mg/kg if insufficient improvement was observed after three infusions. RESULTS: At week 6, only the frequency of anti-histone IgM antibody-positive patients had significantly increased (19 vs 42%, p = 0.009). At week 30, the frequency of patients with ANA had increased from 29% to 69% (p < 0.001), that of patients with anti-dsDNA antibodies had increased from 0% to 3% for IgG (NS) and from 0% to 32% for IgM (p < 0.001); the frequency of antihistone IgG detection had increased from 22% to 32% (p = 0.04) and that of IgM detection, from 18% to 79% (p < 0.001). No lupus-like syndrome was observed. RF decreased significantly (87 IU to 52.5 IU, from baseline to week 30; p < 0.001). No significant difference was observed between the 16 non-responders and the responders, in terms of autoantibody status at baseline and changes with infliximab therapy. CONCLUSION: Infliximab therapy lead to the selective and delayed induction of autoantibodies. This induction was not associated with clinical symptoms until week 30 and did not differ between responders and non-responders.
14667564	Evaluating changes in health status: sensitivity to change of the modified Arabic Health A	2003 Dec	OBJECTIVE: To test the correlation between clinical improvements in patients with rheumatoid arthritis (RA) as defined by the American College of Rheumatology (ACR) response criteria and functional improvements as assessed by functional measures in the modified Arabic version of the Health Assessment Questionnaire (Arabic-HAQ) and to estimate the sensitivity to change of the Arabic-HAQ, in a prospective study. METHODS: Eighty-two patients with active RA were given methotrexate and followed up prospectively for 12 months. ACR response rates and score improvements on the modified Arabic-HAQ were compared. RESULTS: The Arabic-HAQ scores showed significant sensitivity to change after 6 and 12 months and were significantly correlated with the ACR response. Percentages of agreement with ACR response levels were high after 6 months and higher still after 12 months. Standardized effect sizes were 2.34 and 2.84 after 6 and 12 months, respectively. Relative efficiency of the total Arabic-HAQ score in relation to the tender joint count was greater than 1. CONCLUSION: The Arabic-HAQ is valid and sensitive to functional status changes in patients with RA. The results are comparable to those of the original HAQ. Thus, the Arabic-HAQ can be used to evaluate treatments and to identify changes that are important to RA patients.
12817093	Addressing the safety of anakinra in patients with rheumatoid arthritis.	2003 May	Anakinra (Kineret; Amgen Inc., Thousand Oaks, CA) is the first and only recombinant human interleukin-1 receptor antagonist available for therapeutic use. It has been approved by the US Food and Drug Administration and the European Commission for the treatment of patients with rheumatoid arthritis (RA). Anakinra, as an anti-rheumatic therapy, has been assessed in five placebo-controlled clinical trials, either alone or in combination with methotrexate. These trials have shown anakinra to be efficacious and well tolerated by most patients, with the most frequently reported adverse events being mild-to-moderate injection-site reactions that generally resolved rapidly. One of these trials was a large, prospective safety study, which included typical RA patients with a wide variety of co-morbid conditions and receiving concomitant medications. This confirmed that anakinra is a well-tolerated treatment in an RA population representative of that seen by the practising rheumatologist.
12429535	Purine enzymes in patients with rheumatoid arthritis treated with methotrexate.	2002 Dec	OBJECTIVES: To study (a) purine metabolism during treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) and (b) the relation of purine metabolism with efficacy and toxicity of MTX treatment. METHODS: One hundred and three patients with active RA who started treatment with MTX were included. The initial MTX dosage was 7.5 mg/week and raised to a maximum of 25 mg weekly if necessary. The purine enzymes 5'-nucleotidase (5'NT), purine-nucleoside-phosphorylase (PNP), hypoxanthine-guanine-phosphoribosyltransferase (HGPRT), and adenosine-deaminase (ADA) were measured before the start, after six weeks, and after 48 weeks or at study withdrawal. The laboratory results were related to measures of efficacy and toxicity of MTX treatment. RESULTS: Baseline values of 5'NT and PNP (16.9 and 206.8 nmol/10(6) mononuclear cells/h, respectively) were similar to those in former studies. Activities of HGPRT and ADA were relatively low at the start (8.7 and 80.3 nmol/10(6) mononuclear cells/h, respectively). After six weeks purine enzyme activities showed no important changes from baseline. After 48 weeks of MTX treatment a decrease of the enzyme activities of ADA (-21.6 nmol/10(6) mononuclear cells/h; 95% CI -28.6 to -14.7), PNP (-78.9 nmol/10(6) mononuclear cells/h; 95% CI -109.0 to -48.7), and HGPRT (-2.0 nmol/10(6) mononuclear cells/h; 95% CI -3.1 to -0.9) was found. No association was shown between the enzyme activities of ADA, PNP, and HGPRT, and the efficacy or toxicity of MTX treatment. In contrast, enzyme activity of 5'NT showed a decrease in the subgroup of patients discontinuing MTX treatment because of hepatotoxicity. CONCLUSION: MTX treatment in patients with RA leads to a significant decrease of the purine enzyme activities of ADA, PNP, and HGPRT that is not related to the anti-inflammatory efficacy or toxicity of MTX. Hepatotoxicity was related to a decrease in the enzyme activity of 5'NT. These changes may be explained by direct or indirect (via purine de novo and salvage metabolism and the homocysteine pathway) effects of MTX.
15201414	Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.	2004 Jun 17	BACKGROUND: An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study. METHODS: We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses). RESULTS: At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges. CONCLUSIONS: In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48.
14722202	Infliximab treatment for rheumatoid arthritis, with dose titration based on the Disease Ac	2004 Feb	BACKGROUND: Randomised controlled trials have shown that treatment with anti-tumour necrosis factor (anti-TNF) agents is effective in refractory rheumatoid arthritis (RA). OBJECTIVE: To determine the effectiveness of anti-TNF in a general unselected group of patients with refractory RA. METHODS: 68 patients with active RA despite treatment with disease modifying antirheumatic drugs were studied during 12 infliximab infusions. Infliximab (3 mg/kg/infusion) was given every 8 or 6 weeks. Clinical efficacy was assessed by the Disease Activity Score (DAS) index (44 joints). Dose adjustments were based on residual disease activity (DAS score >2.4). The primary end points were the percentage of patients achieving good or moderate response by the EULAR response criteria and the proportion of patients requiring dose adjustment. RESULTS: 20 (29%) patients discontinued treatment owing to side effects, early inefficacy, or other considerations. Among the patients who continued treatment, 27 (56%) and 32 (67%) were responders on the 6th and 12th infliximab infusion, respectively. In the same patients, disease activity gradually improved without modifications in the initial dosing in 10 (21%), whereas in 38 (79%) the dose of infliximab and/or methotrexate was increased. Intensification of treatment led to a significant decrease in the mean DAS score in this group (from 5.27 just before dose modification to 4.54 before the 12th infusion, p<0.002). The EULAR response category improved in only 10/38 (26%), however. CONCLUSIONS: In this initial observational study of patients with RA treated with recommended doses of infliximab, adjustments in treatment were common but not always sufficient to maintain adequate disease control. Longitudinal controlled trials are needed to define the optimal dose escalation in patients with suboptimal response.
12875609	Methotrexate intolerance in elderly patients with rheumatoid arthritis: what are the alter	2003	Rheumatoid arthritis (RA) in the elderly may be mild or severe, with features that are similar to those seen in younger patients. As such, the treatment regimen in the elderly is almost the same as in younger patients. Methotrexate is the most popular disease-modifying antirheumatic drug (DMARD) for the treatment of RA in the US and Europe. It has excellent efficacy and an acceptable toxicity profile. However, a number of patients do not tolerate methotrexate and an alternative DMARD should be chosen. In the elderly, choice of an alternative DMARD should be made after careful consideration of several age-related factors including concomitant diseases, existing medication, drug compliance, and altered age-related physiology and pharmacokinetics. In elderly patients with RA who are unable to tolerate methotrexate, the alternatives are hydroxychloroquine or sulfasalazine for mild-to-moderate disease and cyclosporin or leflunomide for severe disease, given in combination with low-dose oral corticosteroids. This is primarily due to their efficacy combined with a relatively low toxicity profile compared with other DMARDs, such as gold compounds, penicillamine, azathioprine and alkylating agents. Where the above DMARDs are contraindicated, anticytokine therapy should be considered. The therapy of RA is a dynamic process and requires a delicate balance of benefits and risks. Experience and familiarity with the currently available agents, and knowledge of the nature of the disease are necessary in order to make better therapeutic decisions.
14979059	[Current conception of rheumatoid polyarthritis treatment: towards a therapeutic revolutio	2003	Rheumatoid arthritis (RA) is a frequent, heterogenous crippling disease. The diagnosis must be made as soon as possible in order to begin quickly the treatment. The improvement of our knowledge in the immunopathology of RA allowed the development of new biotherapies directed against harmful mediators such as TNF alpha and Interleukin 1. With anti-TNF alpha agents excellent clinical and biological results are observed in methotrexate refractory RA patients in 70% of cases. Moreover these drugs are able to stop the X ray evolution of the disease. They can be considered as a very important new step in the treatment of RA. Other targeted drugs such as anti-IL1, anti-IL6 agents, anti-B lymphocytes monoclonal antibody (Rituximab), CTL4 IgG are already used or under study. In this paper the modern treatment of RA is reviewed with a special emphasis on anti-TNF alpha and anti-IL1 biotherapies.
14500588	HPLC determination of erythrocyte methotrexate polyglutamates after low-dose methotrexate	2003 Oct	BACKGROUND: Methotrexate (MTX) may produce antiarthritic effects through polyglutamation to methotrexate polyglutamates (MTXPGs), a process that covalently attaches sequential gamma-linked glutamic residues to MTX. We sought to develop an innovative HPLC method for the quantification of these metabolites in erythrocytes. METHODS: Two alternative approaches were developed. In the first approach, MTXPGs from 50 micro L of packed erythrocytes were converted to MTX in the presence of plasma gamma-glutamyl hydrolase and mercaptoethanol at 37 degrees C. In the second approach, MTXPG species (up to the hepta order of glutamation) from 100 micro L packed erythrocytes were directly quantified in a single run. In both methods, the MTXPGs were extracted from the biological matrix by a simple perchloric acid deproteinization step with direct injection of the extract into the HPLC. The chromatography used a C(18) reversed-phase column, an ammonium acetate/acetonitrile buffer, and postcolumn photo-oxidation of MTXPGs to fluorescent analytes. RESULTS: Intra- and interday imprecision (CVs) were <10% at low and high concentrations of analytes for both methods. The limit of quantification was 5 nmol/L. In 70 patients with rheumatoid arthritis receiving weekly low-dose MTX, the mean (SD) total MTXPG concentration measured after conversion of MTXPGs to MTX was similar to the total MTXPG concentration calculated from the sum of individual MTXPG species [117 (56) vs 120 (59) nmol/L; r = 0.97; slope = 1.0]. The triglutamate predominated over all other MTXPG species (36% of total), the pentaglutamate was the highest order of glutamation detected, and a stability study revealed no change in the polyglutamation pattern in erythrocytes 48 h after phlebotomy when the specimen was stored at 2-8 degrees C. CONCLUSION: The proposed method for quantification of erythrocyte MTXPGs is rapid, sensitive, and accurate and can be applied to the routine monitoring of MTX therapy.
15645976	Methotrexate induced accelerated nodulosis.	2004 Jul	Methotrexate induced accelerated nodulosis (MIAN) is a rare but unique side effect of methotrexate therapy. There is paucity of data from our country about this entity. We analyzed 14 cases of MIAN and studied its association with gender, rheumatoid factor positivity and dose and duration of methotrexate. Fourteen patients (8 females), 12 with rheumatoid arthritis (8 seropositive), one each with juvenile idiopathic (JIA) and psoriatic arthritis (PsA) were detected to have MIAN during study period. All the patients presented with acute onset of multiple nodules. Radial border of fingers was the most commonly involved site. Disease was inactive in all but two patients at the time of appearance of MIAN. There was no association of MIAN with gender, rheumatoid factor positivity, disease duration, cumulative dose and duration of methotrexate therapy. Two patients each were treated with colchicine, D-penicillamine or hydroxy-chloroquine for 3-6 months without any response. We conclude that MIAN is a benign side effect of methotrexate treatment.
15053231	Reduction of soluble adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin) and vascular e	2004 Jan	INTRODUCTION: The purpose of this study was to determine the effect of repeated infusions of infliximab, a chimeric anti-tumor necrosis factor (anti-TNF)-alpha antibody, on the levels of soluble adhesion molecules and vascular endothelial growth factor (VEGF) in patients with active rheumatoid arthritis (RA). MATERIALS AND METHODS: The treatment design consisted of 9 infusions of infliximab (3 mg/kg) at weeks 0, 2, 6, and every 8 weeks thereafter. All patients had been receiving methotrexate (MTX; 7.5-20 mg/week). Serum levels of soluble intercellular adhesion molecule (sICAM)-1, vascular cell adhesion molecule (sVCAM)-1, E-selectin (sE-selectin), and VEGF were measured by ELISA at weeks 0, 2, 6, 14, and 38 prior to infusion, and at week 62. RESULTS: A remarkable decrease in serum sICAM-1 (p<0.001), sVCAM-1 (p<0.01), sE-selectin (p<0.01) and VEGF (p<0.001) levels was observed in RA patients after the initial dose of infliximab. The second administration of the drug was followed by an even more significant suppression of serum sICAM-1, sVCAM-1, sE-selectin, and VEGF (p<0.001 in all cases). Further infliximab infusions also significantly reduced serum soluble adhesion molecules and VEGF concentrations, although these were less effective. Infliximab treatment induced a significant decrease in the number of monocytes observed until the end of the study. CONCLUSIONS: Our study, besides a rapid suppression of disease activity, showed that serum soluble adhesion molecules and VEGF concentrations are down-regulated following anti-TNF-alpha antibody therapy combined with MTX. Repeated doses of infliximab sustained the reductions in the soluble adhesion molecules and VEGF concentrations, although they were less effective than the first and second infusions of infliximab.
15564880	Contribution of common polymorphisms in reduced folate carrier and gamma-glutamylhydrolase	2004 Nov	We investigated whether polymorphisms in reduced folate carrier (SLC19A1 G80A) and gamma-glutamyl-hydrolase (GGH-401C/T) are predictive of methotrexate polyglutamate (MTXPG) levels in patients with rheumatoid arthritis treated with weekly low-dose methotrexate (MTX). Adult patients treated with MTX were enrolled in a multicentred study. Blood was drawn at the time of the visit, DNA was extracted and red blood cell (RBC) MTXPG levels (up to the penta-order of glutamation) were measured by high-performance liquid chromatography-fluorometry. A G80A polymorphism in SLC19A1 and a -401C/T promoter polymorphism in GGH were measured by polymerase chain reaction-restriction fragment length polymorphism. Multivariate linear and logistic regressions were used to predict long-chain RBC MTXPG3-5. In 226 adult patients receiving MTX (median 15 mg range: 5-25 mg) median RBC long-chain MTXPG3-5 was 56 nmol/l (range < 5-224 nmol/l). A total of 35 patients carried the SLC19A1 80AA genotype whereas 36 patients carried the GGH-401TT genotype. Weekly MTX dose, age, presence of the SLC19A1 80AA and GGH-401TT genotypes predicted independently and significantly MTXPG3-5 levels (global r = 0.38; P < 0.0001). Patients with the GGH-401TT genotype were 4.8-fold [odds ratio (OR) 95% confidence interval (CI) 1.8-13.0; P = 0.002] more likely to have MTXPG3-5 below the group median compared to patient carriers of the GGH-401CC or CT genotype. Conversely, those with the SLC19A1 80AA genotype were 3.4-fold more likely to have MTXPG3-5 levels above the group median compared to those with the SLC19A1 80GG or 80GA genotype (OR CI 95% 1.4-8.4; P = 0.007). These data demonstrate that polymorphisms in SLC19A1 and GGH affect polyglutamation of MTX.