Methotrexate In Rheumatoid Arthritis Research Articles

Subsequent Entry Biologics – Opportunities and Challenges

Currently, infliximab and adalimumab are the two antitumour necrosis factor (TNF) agents available in Canada for the treatment of Crohn disease and ulcerative colitis (adalimumab is not yet licensed for use in ulcerative colitis). At least one more anti-TNF monoclonal antibody (golimumab) is awaiting approval. Furthermore, the gut-specific antiadhesion antibody vedolizumab is also on the horizon for inflammatory bowel disease (IBD). Subsequent entry biologics (SEBs), also known as biosimilars, are monoclonal antibodies that are similar but not identical to the reference biologic drug (RBD). With the patents for anti-TNF antibodies, such as infliximab, coming to an end, anti-TNF SEBs have been manufactured and an important overview of this has been provided by Devlin et al (1) (pages 567–571) in the current issue of the Journal. Given the cost of biological drugs, the potential for SEBs to lower cost, both by virtue of lower cost of SEBs and competitive lowering of cost of RBDs, will be welcome. SEBs are already on the market in some geographical jurisdictions, such as South Korea, and are well on the way to approval in Europe. There are, however, certain considerations that may be of clinical relevance to practising gastroenterologists in Canada, which include the following: Are the molecular structures of SEBs and RBDs comparable?: Subtle differences in structure, such as fucosylated forms, may affect antibody-dependent cell-mediated cytotoxicity and binding to FcγR, which may affect drug clearance and serum drug levels. Therefore, SEBs cannot be viewed as a generic RBD (2). It is also not clear whether the ‘molecular drift’ between SEBs and RBDs may widen over time as part of the manufacturing process. Are the pharmacokinetics of SEBs and RBDs comparable?: RBDs are used in combination with methotrexate in rheumatoid arthritis, as monotherapy in ankylosing spondylitis, and often in psoriasis and in combination with azathioprine in IBD. The doses are different for different indications in the case of RBDs. Therefore, comprehensive pharmacokinetic studies at low and high dose levels, as well as single and multiple doses, may be required to ensure the comparability of SEBs and RBDs. Serum drug levels are critical for the efficacy of monoclonal antibodies in immune-mediated inflammatory diseases (3). Are trial designs sufficiently robust to test efficacy comparability of SEBs and RBDs?: Equivalency studies with sufficiently narrow comparability margins to establish efficacy may require very large studies, which are difficult to conduct, and would compete for the same patients who may otherwise enter studies for the development of novel compounds for the treatment of IBD. For logistical reasons, such very large equivalence studies may not be performed. Are the immunogenicities of SEBs and RBDs comparable?: Immunogenicity of biological drugs is an important consideration and depends on the molecular structure of the monoclonal antibody, concomitant drugs such as methotrexate or azathioprine, the nature of the immune-mediated inflammatory disease, as well as the assay platform and test method. The assay methodology should be capable of detecting unique antidrug antibody to SEB; otherwise, the immunogenicity may be underestimated. It will also be important to determine clearly whether the antidrug antibodies cross-react between RBDs and SEBs. Can SEB drugs be extrapolated from one indication to another?: The precise mechanism of action, site of action, dose of monoclonal antibody and safety profile may have subtle differences among different immune-mediated inflammatory diseases. Therefore, extrapolation of efficacy based on clinical trials for one indication, such as rheumatoid arthritis, to another indication, such as ulcerative colitis or Crohn disease, may be difficult. On the other hand, conducting large separate clinical trials in different immune-mediated inflammatory diseases may be extremely expensive. Will the logistical support for administration be similar between RBDs and SEBs?: In Canada, gastroenterologists rely heavily on a support network from the sponsor company for administration of intravenous monoclonal antibodies. The comparability of such support networks between SEBs and RBDs will be important to practising gastroenterologists. Gastroenterologists treating IBD need to watch this rapidly evolving area with interest. Any reduction in cost of treatment with monoclonal antibodies will be welcome. The unique way in which the SEB drugs will have to considered, as described by Devlin et al (1) is, however, alien to gastroenterologists who have previously considered generic 5-aminosalicylates in their practice. A basic understanding of the issues will ensure that gastroenterologists are prepared for SEBs. Switching a well-controlled patient on a biological drug to another biological drug of the same class may be inadvisable based on the experience of the SWITCH study, which switched well-controlled patients on infliximab to adalimumab (4).

Biologic agents in rheumatoid arthritis: temporal trend of incremental benefits.

In evaluating the efficacy of biologic agents in rheumatoid arthritis (RA), one interesting feature of the meta-analysis by Favalli and colleagues [Favalli et al. 2012] is that outcomes were expressed as damage progression (namely, annual radiographic progression [ARP] rate). Although expressing outcomes this way raises a number of methodologic issues, the methods adopted by Favalli and colleagues were accurate and convincing, and so their analysis offered a new perspective for interpreting the benefits of biologic agents. The initial analysis of Favalli and colleagues included 12 studies and found a mean difference of nearly −30% in the ARP rate for biologics in comparison with methotrexate as well as a high heterogeneity (I2 = 99%). After excluding the two most asymmetrical studies in the funnel plot, the plot’s results were improved and the mean improvement was less pronounced (mean difference = −18.7%; 95% confidence interval: −29.9% to 7.44%); however, heterogeneity remained very high (I2 = 100%). To reduce heterogeneity, Favalli and colleagues separated the 12 trials into a subgroup including studies on early disease (5 trials) and a subgroup including studies on late disease (7 trials). Even after this separation, heterogeneity remained high (I2 = 97% and 99% for the two subgroups, respectively). We have re-analysed the same data included in Favalli and colleagues’ study by application of metaregression. This statistical technique was applied as described previously [Messori et al. 2012a, 2012b; Vasques et al. 2012]. In performing our analysis, the metaregression first assessed two covariates (‘year of publication’ and ‘disease stage’ classified as early versus late) and its stepwise process left out the covariate ‘disease stage’ (since its significance, p = 0.464, was far from the prespecified threshold of p = 0.10). At the next step, the results of metaregression indicated that ‘year of publication‘ was a significant covariate. Figure 1 illustrates these results. According to the regression line, the values of mean difference varied from −65% in 2000 to −10% in 2012. A smaller and smaller absolute difference with time (from approximately 65% in 2000 to 10% in 2012) means that the incremental effectiveness (or improvement) of biologics has decreased over the time interval examined. More importantly, this annual loss of improvement was clinically relevant and showed a clear statistical significance (annual loss of improvement 4.59%; p = 0.014). Interestingly enough, the residual heterogeneity found in our analysis after incorporation of this covariate was at I2 = 84.8%; as compared with the I2 values found by Favalli and colleagues, there was a reduction in heterogeneity, although our value remained high. Figure 1. Meta-regression analysis of temporal trends of mean difference in effectiveness between biologics and methotrexate in rheumatoid arthritis from 2000 to 2012 (12 randomized trials; data obtained from Tables 3 and 4 of Favalli et al. [2012]). The values ... In conclusion, the analysis of Favalli and colleagues has the merit of focusing on an important clinical outcome. Our metaregression of the same data suggests another interpretation, i.e. that biologics have apparently reduced, with time, their incremental benefit over methotrexate. While our findings are difficult to interpret and could simply be coincidental, investigating the main determinants of the efficacy of biologics in RA remains a matter of further study. In this framework, the various hypotheses presented by Favalli and colleagues are another step forward in the knowledge of treatments for this disease.

Efficacy of concurrent administration of cilostazol and methotrexate in rheumatoid arthritis: Pharmacologic and clinical significance

AimsThis study aimed to assess the beneficial effects of the concurrent administration of cilostazol and methotrexate (MTX) on the synovial fibroblasts obtained from patients with rheumatoid arthritis (RA), and in a mouse model of collagen-induced arthritis (CIA). Main methodsProduction of TNF-α, IL-1β, IL-6 and MCP-1 on synovial fibroblasts from RA patients was determined by RT-PCR. Cell proliferation, viability and apoptosis were measured. Anti-arthritic effects were evaluated in CIA mice. Key findingConcurrent use of cilostazol and MTX effectively suppressed proliferation and cell viability associated with enhanced apoptosis of synovial fibroblasts and significantly suppressed cytokine production, including TNF-α, IL-1β, IL-6, and MCP-1 in an additive manner. In line with these findings, LPS-induced increased expression of NURR1 mRNA and protein were suppressed by cilostazol and MTX in accordance with suppression of NF-κB p65 activity. These suppressed effects were reversed by KT5720 (cAMP-protein kinase inhibitor) and ZM 241385 (A2A receptor antagonist), respectively. In CIA mice, treatment with cilostazol, MTX and their combination significantly decreased clinical signs with improvement of histopathological status in the paw of mice, accompanied by reduced serum cytokine levels. Likewise, following concurrent administration, CD68 (+)-cell recruitment, proteoglycan depletion and osteoclast formation were significantly suppressed in association with repressed RANKL expression in the joints of CIA mice. SignificanceIn conclusion, a combination of cilostazol and MTX may provide an effective therapeutic strategy for the suppression of inflammation and the prevention of joint damage in RA via activation of the cAMP-dependent protein kinase in the synovial fibroblasts.

84-Year-Old Woman With Chest Pain

An 84-year-old woman presented to the emergency department with an 8-hour history of persistent substernal chest pain. The pain intensity was rated a 6 on a scale of 1 to 10, radiated to the shoulder blades, and was worse with deep breathing and lying flat. She denied dyspnea, orthopnea, palpitations, or lower-extremity edema. She had no history of cardiac disease. Her medical history was notable for well-controlled rheumatoid arthritis and hypertension. Her medications included triamterene and hydrochlorothiazide (37.5 and 25 mg/d) for hypertension and methotrexate for rheumatoid arthritis (15 mg/wk), which she had stopped taking 8 weeks earlier after recent hip surgery.

Serum adenosine deaminase in patients with rheumatoid arthritis treated with methotrexate.

Objective:Recently, adenosine deaminase (ADA) is introduced as helpful marker in diagnosis, prognosis, and monitoring of treatment in rheumatoid arthritis (RA). The aim of this study was to determine the efficacy of the serum ADA in diagnosis, prognosis, and monitoring of treatment with methotrexate (MTX) in RA.Methods:This was a self-controlled clinical trial conducted in university hospitals of Isfahan, Iran. The serum level of ADA, erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) were measured for 70 patients with active RA (Disease Activity Score-28 [DAS28] > 3/2). After three months of MTX treatment and disease remission (DAS28 < 2.6) these markers were measured again. ANCOVA multiregression and paired t-test were used to compare and evaluate the mean level and correlation of ADA, ESR, IgM-RF, and DAS before and after RA remission.Findings:The mean value for ADA activity was significantly higher than the normal one compared with other studies. Significant decreases were seen in values of ADA, ESR, RF, visual analogue scale (VAS), and DAS after remission. Also, the correlation coefficient between the values of ADA with ESR and DAS were statistically significant in baseline. Moreover, the statistically significant correlation between ADA and ESR, VAS, and DAS were seen after remission. No correlation was found in the case of the dosage of MTX with the value of ADA.Conclusion:It was concluded that ADA may be considered useful as a marker in diagnosis, prognosis, and monitoring of treatment with Methotrexate in RA.

Markers of Treatment Response to Methotrexate in Rheumatoid Arthritis: Where Do We Stand?

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, despite its efficacy and affordability, additional DMARDs or biologic agents are often required in order to achieve the recommended goals of low disease activity or remission. Although well tolerated by most, some patients develop important side effects such as cytopenias, gastrointestinal adverse events (stomatitis, nausea), or abnormal liver function tests, which may limit its use and may result in additional health care costs. Given the clinical implications of widespread use of MTX in RA, various studies have evaluated the role of potential biomarkers in predicting treatment effectiveness of MTX. These biomarkers include RBC MTX polyglutamate (PG) levels; genetic variation in genes from relevant biological and metabolic pathways; gene expression profiles; serum proteins. This paper provides an update on the current data regarding biomarkers of treatment response to MTX.

Monocyte populations as markers of response to adalimumab plus MTX in rheumatoid arthritis

IntroductionThe treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor alpha (TNFα) biological drugs has dramatically improved the prognosis of these patients. However, a third of the treated patients do not respond to this therapy. Thus, the search for biomarkers of clinical response to these agents is currently highly active. Our aim is to analyze the number and distribution of circulating monocytes, and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets in methotrexate (MTX) non-responder patients with RA, and to determine their value in predicting the clinical response to adalimumab plus MTX treatment.MethodsThis prospective work investigated the number of circulating monocytes, and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets, in 35 MTX non-responder patients with RA before and after three and six months of anti-TNFα treatment using multiparametric flow cytometry. The number of circulating monocytes in an age- and sex-matched healthy population was monitored as a control.ResultsNon-responder patients with RA show an increased number of monocytes and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets after three months of adalimumab plus MTX treatment that remained significantly increased at six months. In contrast, significant normalization of the numbers of circulating monocytes was found in responders at three months of adalimumab plus MTX treatment that lasts up to six months. CX3CR1 expression is increased in monocytes in non-responders. At three months of anti-TNFα treatment the number of circulating monocytes and their subsets was associated with at least 80% sensitivity, 84% specificity and an 86% positive predictive value (PPV) in terms of discriminating between eventual early responders and non-responders.ConclusionsThe absolute number of circulating monocytes and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets at three months of adalimumab plus MTX treatment, have a predictive value (with high specificity and sensitivity) in terms of the clinical response after six months of anti-TNFα treatment in patients with RA.

The Impact of Folate Status on the Efficacy of Colorectal Cancer Treatment

Over the past three decades, numerous reports have addressed several aspects of drug resistance phenomena. However, little is known regarding the impact that dietary components and nutritional supplements have on the mechanisms of resistance that malignant cells develop to chemotherapeutic agents. The increased fortification of cereals, grains and bread with folic acid (FA) has resulted in a marked rise in folate levels in blood and tissues. Vitamin fortification that includes FA is rather commonly used by cancer patients, but FA is also used to protect against pemetrexed induced side effects in the treatment of non-small cell lung cancer and mesothelioma or that of the antifolate methotrexate in rheumatoid arthritis. Moreover, the reduced folate leucovorin (LV, 5-formyltetrahydrofolate) is also used along with 5-fluorouracil in the treatment of colorectal cancer. Likewise, LV is used to reduce toxicity of methotrexate in the treatment of leukemia. FA can also increase efficacy of unrelated regimens, containing cisplatin. Hence there is growing evidence that dietary supplements as folic acid, can mimic, intensify, or attenuate the effects of unrelated chemotherapeutic agents. The aim of this review is to highlight some new insights in the cellular and molecular mechanisms affected by folate status, leading to chemotherapy resistance, especially towards antifolates in colorectal cancer treatment. This encompasses the effect of folate status on drug export, as well as on the increased expression of mutated target enzymes involved in folate metabolism and on the augmentation of cellular folate pools that impair polyglutamylation of antifolates, ultimately affecting treatment efficacy.

The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population

Objective: Methotrexate (MTX) is the first-choice drug for the treatment of rheumatoid arthritis (RA) patients. However, 30% of RA patients discontinue therapy within 1 year, usually because of adverse effects. Previous studies have reported conflicting results on the association of polymorphisms in the MTHFR gene with the toxicity of MTX in RA. The aim of this study was to assess the involvement of the C677T and A1298C polymorphisms in the MTHFR gene in the toxicity of MTX in a Spanish RA population.Methods: The study included retrospectively 468 Spanish RA patients treated with MTX. Single nucleotide polymorphism (SNP) genotyping was performed using the oligonucleotide microarray technique. Allele and genotype association analyses with regard to MTX toxicity and a haplotype association test were also performed.Results: Eighty-four out of the 468 patients (18%) had to discontinue therapy due to adverse effects or MTX toxicity. The C677T polymorphism (rs1801133) was associated with increased MTX toxicity [odds ratio (OR) 1.42, 95% confidence interval (CI) 1.01–1.98, p = 0.0428], and the strongest association was shown in the recessive model (OR 1.95, 95% CI 1.08–3.53, p = 0.0246). The A1298C polymorphism (rs1801131) was not associated with increased MTX toxicity (OR 0.94, 95% CI 0.65–1.38, p = 0.761). A borderline significant risk haplotype was found: 677T-1298A (OR 1.40, 95% CI 1.00–1.96, p = 0.0518).Conclusion: These results demonstrate that the C677T polymorphism in the MTHFR gene is associated with MTX toxicity in a Spanish RA population.

FDG PET/CT in a Patient With Spontaneous Remission of Methotrexate-Associated Lymphoproliferative Disorders After Interruption of Methotrexate

We report a case that fluorodeoxyglucose positron emission tomography (FDG PET)/computed tomography (CT) depicted systemically multiple lesions of methotrexate (MTX)-associated lymphoproliferative disorders. A 70-year-old man receiving MTX for rheumatoid arthritis complained of neck swelling. FDG PET/CT revealed multiple FDG-avid lesions in lymph nodes, lungs, bones, and muscles. Lesions in bones and muscles were not detected on X-CT. Final diagnosis of cervical node was confirmed as MTX-associated lymphoproliferative disorders. FDG PET/CT performed 148 days after discontinuing MTX demonstrated complete remission.

How to Investigate and Follow Up Undifferentiated Peripheral Inflammatory Arthritis? 3e Initiative 2008-2009: Systematic Reviews and Clinical Algorithm

The 3e (Evidence, Expertise, Exchange) Initiative in Rheumatology is a multinational effort aimed at generating evidence-based recommendations for common clinical problems. It integrates systematically generated evidence with expert opinion of a broad panel of international rheumatologists. Phases I and II of the 3e Initiative addressed, respectively, the management of ankylosing spondylitis and the use of methotrexate in rheumatoid arthritis. The objective of phase III 2008–2009 was to develop practical recommendations for management of patients with undifferentiated peripheral inflammatory arthritis (UPIA). Patients with UPIA are commonly seen in rheumatology practice and often remain without a specific diagnosis. Their management varies considerably among rheumatologists; there are no widely accepted criteria for diagnosis and no guidance on how to investigate and follow up these patients. In this international project, experts agreed to label as “undifferentiated” those patients with at least one …

メトトレキサート関連リンパ増殖性疾患の４例

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) involves lymphoid proliferations or lymphomas in subjects with autoimmune disease, especially rheumatoid arthritis (RA) treated with methotrexate (MTX). The relationship of MTX medication and LPD development has been discussed, and we report four cases of MTX-LPD. Case 1: A 54-year-old woman administered MTX for RA since April 2007 was seen for right cheek and submandibular swelling in August 2008. Magnetic resonance imaging (MRI) showed cervical lymphadenopathy, necessitating lymph node biopsy revealing diffuse large B-cell lymphoma. MTX was discontinued and lymph nodes shrank within a month. In May 2009, general lymphadenopathy relapsed and she underwent chemotherapy. Case 2: A 63-year-old man administered MTX for RA since June 1999 was seen for 1-year right submandibular swelling in January 2009. MRI showed submandibular lymph node swelling, necessitating lymph node removal yielding a pathological diagnosis of MTX-LPD similar to nodular lymphocyte predominant Hodgkin lymphoma. MTX was discontinued and the man has shown no sign of recurrence. MTX-LPD incidence is expected to increase as MTX is used increasingly to treat RA. We should therefore take MTX-LPD in consideration when examining subjects treated with MTX.

Increased Peripheral T Cell Responses to EBV-Infected Cells with Frequent Detection of EBV-DNA In Plasma and Viral mRNA In Peripheral B-Cells In Immunocompetent EBV-Positive Diffuse Large B-Cell Lymphoma Patients

AbstractAbstract 4163 Introduction:It is well known that immunocompromised patients(pts) such as post-transplantation or HIV infection are at increased risk of EBV-associated B-cell lymphoproliferaitive disorders. However, the immunological status of immunocompetent EBV-positive diffuse large B-cell Lymphoma (DLBCL) has not been well elucidated. For example, EBV-positive DLBCL in the elderly is defined as an EBV-positive clonal B-cell lymphoid proliferation occurring in pts more than 50 years of age and without any known immunodeficiency in WHO classification 2008, accounting for 5 – 10% of DLBCL in Japan. This disease is speculated to be related to the immunological deterioration accompanying the aging process. We conducted a multi-center prospective study to assess EBV status and the T cell response to EBV of peripheral blood (PB) in EBV-positive DLBCL in comparison with EBV-negative DLBCL pts and normal old-healthy persons (old-HPs). Patients and Methods:Fifteen newly-diagnosed pts with EBV-positive DLBCL, 8 pts with EBV-negative DLBCL, and 16 old-HPs were enrolled. Median ages of pts with EBV-positive DLBCL, pts with EBV-negative DLBCL, and old-HPs were 74.5 years (range 29–82 years), 71 years (48-79), and 65 years (60-74), respectively. Among the 15 pts with EBV-positive DLBCL, 2 were pyothorax-associated lymphoma, 2 were treated with methotrexate for rheumatoid arthritis, and the remaining 11 pts were without past histories predisposing to immunodeficiency. The diagnosis of EBV-positive DLBCL was made by positive signals for in situ hybridization using EBV-encoded small RNA (EBER) on paraffin section. To analyze T cell reactivity to autologous EBV-infected B-cell lymphoblastoid cell lines (LCL), CFSE-labeled peripheral blood mononuclear cells (PBMCs) were co-cultured with irradiated autologous LCL, and the division indices (DI) of CD4+ and CD8+ T cells were determined on day 5 (Cytometry 34:143, 1998). Percentage of proliferating CFSElow IFN-γ+CD4+ T cells and CFSElow IFN-γ+CD8+ T cells was assessed on day 7. EBV DNA load in PBMCs and plasma was determined by quantitative real-time PCR. CD19+ B cells were separated from of PBMCs by immunomagnetic sorting, and viral mRNA expression of B cells was quantified by one-step multiplex real-time RT-PCR. Results:(1) Plasma EBV-DNA was detectable in 13 of the 15 EBV-positive DLBCL pts but in none of the 8 EBV-negative DLBCL pts or the 16 old-HPs. Copy number of EBV-positive DLBCL was significantly higher than EBV-negative DLBCL (p<0.00001) or old-HPs (p=0.0001). EBV-DNA in PBMC was positive in 10 of the 15 EBV-positive DLBCL pts, 2 of 8 EBV-negative DLBCL pts, and 2 of 15 old-HPs. (2) EBER1 of PB B cells was detected in all 10 EBV-positive DLBCL pts, 4 of 7 EBV-negative DLBCL pts, and 7 of 14 old-HPs. BamHI A rightward transcripts (BARTs) of B-cells was detected in 8 of 10 EBV-positive DLBCL pts, 3 of 10 EBV-negative DLBCL pts, and 2 of 14 old-HPs. Latent membrane protein 2 (LMP2) of B cells was detected in 2 of 10 EBV-positive DLBCL pts, 2 of 14 old-HPs, and none of 5 EBV-negative DLBCL pts. LMP1 of B cells was detected in 1 of 10 EBV-positive DLBCL pts, none of 7 EBV-negative DLBCL pts, and none of 14 old-HPs. EBV-encoded nuclear antigen 1 (EBNA1) or EBNA2 were not detected in any of the pts nor old-HPs. (3) DI of CD4+ T cells for 5 days in EBV-positive DLBCL (median 1.41) was significantly higher than in old-HPs (median 0.53) (p=0.0009), and DI of CD8+ T cells of EBV-positive DLBCL (median 1.94) showed a higher tendency than old-HP (median 1.35). (4) Percentage of CFSE-low IFN-γ+CD4+ T cells in EBV-positive DLBCL (median 9.8%) was significantly higher than in old-HPs (median 2.2%) (p=0.002), and percentage of CFSE-low IFN-γ+CD8+ T cells in EBV-positive DLBCL (median 12.0%) was significantly higher than in old-HPs (median 6.6%)(p=0.025). Conclusions:Measurement of the plasma EBV-DNA copy number is a good indicator for the diagnosis of EBV-positive DLBCL, and the frequent detection of EBV viral mRNA of peripheral B-cells in EBV-positive DLBCL pts might be associated with greater viral load. Proliferative and INF-γ secreting responses of both peripheral CD4+ T cells and CD8+ T cells to EBV-infected cells were increased in EBV-positive DLBCL compared to old-HPs, which might be driven by an elevated viral load. These findings suggest that systemic immunological reaction to EBV might be intact in EBV-positive DLBCL. Disclosures:No relevant conflicts of interest to declare.

PubMed had a higher sensitivity than Ovid-MEDLINE in the search for systematic reviews

Objective To compare the performance of Ovid-MEDLINE vs. PubMed for identifying randomized controlled trials of methotrexate (MTX) in patients with rheumatoid arthritis (RA). Study Design and Setting We created search strategies for Ovid-MEDLINE and PubMed for a systematic review of MTX in RA. Their performance was evaluated using sensitivity, precision, and number needed to read (NNR). Results Comparing searches in Ovid-MEDLINE vs. PubMed, PubMed retrieved more citations overall than Ovid-MEDLINE; however, of the 20 citations that met eligibility criteria for the review, Ovid-MEDLINE retrieved 17 and PubMed 18. The sensitivity was 85% for Ovid-MEDLINE vs. 90% for PubMed, whereas the precision and NNR were comparable (precision: 0.881% for Ovid-MEDLINE vs. 0.884% for PubMed and NNR: 114 for Ovid-MEDLINE vs. 113 for PubMed). Conclusion In systematic reviews of RA, PubMed has higher sensitivity than Ovid-MEDLINE with comparable precision and NNR. This study highlights the importance of well-designed database-specific search strategies.

ORIGINAL ARTICLE: Lack of association between elevated mean red cell volume and haematological toxicity in patients receiving long‐term methotrexate for rheumatoid arthritis

It has been suggested that elevated mean red cell volume (MCV) may be a predictor of haematological toxicity in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). We wished to identify whether there was an association between MCV, red cell folate and haematological toxicity in patients on MTX monotherapy for the long-term management of RA. Evidence of haematological toxicity was sought by note review of patients recruited in a cross-sectional study of MTX monotherapy in RA. Retrospective data included MCVs from before MTX initiation and after 3 and 6 months of treatment. Data were collected prospectively every 6 months for up to 2 years after enrolment. Any record of cytopenia or the development of haematological malignancy was recorded from commencement of MTX until the present day. Red cell folate concentrations were tested on enrolment to the study. A total of 165 patients was included, 74.5% female, median disease duration 7 years (range 3 months-57 years). The median duration of MTX treatment was 74.9 months (range 10-241 months) giving 1030.2 patient-years of MTX exposure. Twenty-four patients (14.5%) had a MCV > 98 fL on study entry. Evidence of haematological abnormality was found in six patients (3.6%); chronic lymphocytic leukaemia (1), persistent lymphocytosis (1), persistent monocytosis (1) and neutropenia (3). There was no association between red cell folate or MCV and haematological toxicity. Neutropenia and pancytopenia are rare side-effects of MTX therapy in this cohort. Elevated MCV or low mean red cell folate does not appear to be associated with haematological malignancy or toxicity in this cohort of patients on long-term MTX therapy.

Race and Methotrexate Pharmacogenetics in Rheumatoid Arthritis

To the Editor: Fisher and Cronstein are to be commended for their recent metaanalysis on methylenetetrahydrofolate reductase (MTHFR) polymorphisms and methotrexate (MTX) toxicity in rheumatoid arthritis (RA)1. Their work exposes the lack of sound pharmacogenetic data on MTX in RA and underscores that there is a long way to go before MTX pharmacogenetics is ready to guide clinical decision-making in RA. In the discussion, the authors note the paucity of data in the literature to determine whether the presence or absence of a single-nucleotide … Address correspondence to Dr. Ranganathan. E-mail: prangana{at}dom.wustl.edu

Associations between the C677T and A1298C Polymorphisms of MTHFR and the Efficacy and Toxicity of Methotrexate in Rheumatoid Arthritis

The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be associated with the toxicity and efficacy of methotrexate in rheumatoid arthritis (RA), although the results of previous studies have been inconsistent. The aim of this study was to explore whether the C677T and A1298C polymorphisms of MTHFR play a role in the toxicity and efficacy of methotrexate in RA. The authors identified and evaluated studies conducted on the association between the C677T and A1298C polymorphisms of MTHFR and on the toxicity and efficacy of methotrexate in RA. A meta-analysis was then conducted to compare the toxicity and efficacy of methotrexate with respect to the 677CC and 677CT/TT genotypes and the 1298AA and 1298AC/CC genotypes. Eight studies, which included a total of 1514 patients with RA, were included in this meta-analysis. Meta-analysis did not show any association between the C677T and A1298C polymorphisms of MTHFR and the toxicity of methotrexate in RA in all patients or in Asian patients. The odds ratios (ORs) for adverse effects with 677CC versus 677CT/TT in all patients and in Asian patients were 0.633 (95% CI 0.325, 1.234; p = 0.180) and 0.621 (95% CI 0.233, 1.655; p = 0.341), respectively. The ORs for adverse effects with 1298AA versus 1298AC/CC in all patients and in Asian patients were 0.942 (95% CI 0.479, 1.851; p = 0.861) and 0.978 (95% CI 0.569, 1.681; p = 0.936), respectively. Heterogeneities were evident among the included studies. In addition, no association was found between the C677T and A1298C polymorphisms and the efficacy of methotrexate in RA in all patients. Our meta-analysis including 1514 patients with RA found no association between the C677T and A1298C polymorphisms of MTHFR and the toxicity and efficacy of methotrexate in RA. Because of the paucity of pharmacogenetic data, further studies are needed to determine the role of MTHFR polymorphisms in the toxicity and efficacy of methotrexate.

CYCLOSPORINE A IN RHEUMATOID ARTHRITIS: CURRENT DATA

Despite the advent of the new class of medications, such as gene engineering biologicals, the use of traditional essential anti-inflammatory drugs (EAID) remains the most important method of pathogenetic therapy for rheumatoid arthritis (RA). Apart from methotrexate (MT) that is the gold standard of treatment for RA, there are a number of other effective EAIDs, including cyclosporine A (CsA, Sandimmun). The review deals with the practical aspects of using CsA in RA. Particular emphasis is laid on the capacities of combined basic therapy with CsA and MT in early RA and on the use of CsA in patients with concomitant chronic viral diseases (including viral hepatitis C).

An update on methotrexate

Methotrexate (MTX) has been used for the treatment of rheumatoid arthritis (RA) for about three decades now. MTX is one of the most effective and commonly used medicines to treat various forms of arthritis and other rheumatic conditions. MTX was shown to improve signs and symptoms of RA, disease activity and function, to a similar degree as the tumor necrosis factor blockers, and it inhibits radiographic progression to a smaller degree than the antitumor necrosis factor agents. MTX is considered as the anchor drug among the disease-modifying antirheumatic agents, and it is internationally accepted as the first choice in the management of RA. This review was performed on the basis of a PubMed literature search looking at all publications on MTX and arthritis in 2008. MTX seems to even prolong the life span of patients who tolerate the drug and have clinical benefit from this therapy; this may partly be explained by beneficial effects on cardiovascular mortality. The reason for this may well be the suppression of inflammation, but direct atheroprotective effects of MTX may also play a role. MTX is used as monotherapy and in combination with other disease-modifying antirheumatic agents or biologic agents such as the antitumor necrosis factor agents. The 'early' use of MTX within 5 years after disease onset is clearly associated with improved outcomes. The management of RA should include an early strong suppression of inflammation and continuously a tight control strategy. The pharmacodynamics and kinetics of MTX are still incompletely understood. In this review, we especially cover the following themes: new clinical studies on the use of MTX in RA, the use of MTX in other rheumatic conditions, prediction of response to MTX, optimal dosage, MTX use in the elderly, the mechanism of action, the pharmacokinetics and the pharmacogenetics of MTX, the prevention of side effects, and the overall long-term safety.

Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature

Objectives:To review systematically the available literature on the optimal dosage and route of administration of methotrexate in patients with rheumatoid arthritis (RA), as an evidence base for generating clinical practice...