Old drugs, old problems: Where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs

BMC Medicine (Impact Factor: 7.25). 01/2013; 11(1):17. DOI: 10.1186/1741-7015-11-17
Source: PubMed


Methotrexate (MTX) is the central drug in the management of rheumatoid arthritis (RA) and other immune mediated inflammatory diseases. It is widely used either in monotherapy or in association with other synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs). Although comprehensive clinical experience exists for MTX and synthetic DMARDs, to date it has not been possible to preview correctly whether or not a patient will respond to treatment with these drugs. Predicting response to MTX and other DMARDs would allow the selection of patients based on their likelihood of response, thus enabling individualized therapy and avoiding unnecessary adverse effects and elevated costs. However, studies analyzing this issue have struggled to obtain consistent, replicable results and no factor has yet been recognized to individually distinguish responders from nonresponders at treatment start. Variables possibly influencing drug effectiveness may be disease-, patient- or treatment-related, clinical or biological (genetic and nongenetic). In this review we summarize current evidence on predictors of response to MTX and other synthetic DMARDs, discuss possible causes for the heterogeneity observed and address its translation into daily clinical practice.

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Available from: João Fonseca, Mar 29, 2014
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    • "Some studies suggest that ESR level, mentioned as a biomarker for chronic systemic inflammation as well as a parameter of disease activity, correlated with responsiveness to MTX (reviewed by Romao et al.) [37]. In the present study, we see that the effect of KIR2DS4f is strongest in individuals with medium susceptibility to the therapeutic effect of MTX characterized by an intermediate level of ESR. "
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    ABSTRACT: Background KIR genes coding for natural killer cell immunoglobulin-like receptors, KIR, influence the effector and regulatory function of NK cells as well as some subpopulations of T lymphocytes (e.g. CD4+CD28-KIR+) depending on presence of ligands (particularly HLA-C molecules). KIR-KIR ligand interaction may lead to the development of autoimmune disorders, including rheumatoid arthritis (RA). However, their role in the response of RA patients to methotrexate therapy is not known. Methods KIR genes and KIR-ligand (HLA-C C1/C2 allomorphs) genotyping was performed using the PCR-SSP method in 312 RA patients (179 classified as good responders and 133 as poor responders using DAS28 criteria). Thus, we evaluated the association of KIR genes and HLA-C allomorphs with the response to methotrexate (MTX) treatment. Results We observed that patients possessing the full-length KIR2DS4 (KIR2DS4f) gene had a lower chance of responding in comparison to KIR2DS4f-negative cases. This phenomenon was observed both in erosive disease (ED) and rheumatoid factor (RF) positive and in ED- and RF-negative patients. Interestingly, the observed effect of the KIR2DS4f gene was strongest in individuals possessing medium values (20-33 mm/h) of the erythrocyte sedimentation rate (ESR). Patients with high ESR values had low probability and, in contrast, patients with low ESR had a high probability of MTX response, and the presence of KIR2DS4f did not affect their outcome. Additionally, we show that the KIR2DS4f effect did not depend on the presence of either C1 or C2 allomorphs. Conclusion Our results suggest that the response of RA patients with medium ESR values to MTX treatment may be dependent on the full-length KIR2DS4 gene.
    BMC Musculoskeletal Disorders 07/2014; 15(1):256. DOI:10.1186/1471-2474-15-256 · 1.72 Impact Factor
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    • "The factors that are possibly influencing disease course and therapeutic outcome can be classified into (1) clinicopathological variables, which can be divided into patient-related variables (age, gender, ethnicity, and comorbidities), disease-related variables (duration, activity, disability, and biomarkers), and treatment-related variables (compliance, dose, and previous drugs used) [3] [4] [5] [6] [7] [8] [9], and (2) genetic factors, such as genetic polymorphisms implicated in key MTX pathway genes [2, 10–15]. Several studies have been performed in order to evaluate the influence of clinicopathological variables in clinical response to MTX [3] [5] [7] [16] [17]; nevertheless, there is no consensus on which factors can be used as predictors [18]. Pharmacogenomics has raised great interest and, in fact, some studies have attempted to clarify the influence of genetic variations on clinical response to MTX [19]. "
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    ABSTRACT: Objective: Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients. Methods: Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables. Results: Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response. Conclusion: Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment.
    BioMed Research International 05/2014; 2014(Article ID 368681):11 pages, 2014. DOI:10.1155/2014/368681 · 1.58 Impact Factor
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    ABSTRACT: The collagenase cathepsin K has been shown important in the pathogenesis of rheumatoid arthritis (RA). Icariin is the major pharmacologically active flavonol diglycoside of Herba Epimedii, an herb used in Chinese traditional medicine to treat arthritis. We investigated whether icariin can inhibit the protease activity of cathepsin K and its effects on a murine model of collagen-induced arthritis (CIA). Six-week old female BALB/C mice were immunized with type II collagen and treated with vehicle alone icariin (25mg/kg) for 21 days; a control remained untreated. Serum concentrations of type I collagen C-terminal telopeptide (CTX-I) and cartilage oligomeric matrix protein (COMP) and urinary concentrations of deoxypyridinoline (DPD) were measured, and disease severity was assessed. Compared with immunized, untreated mice, immunized icariin-treated mice had significantly lower urinary DPD (~25%, p<0.01) and serum COMP (~11.9%, p<0.01) concentrations, with serum CTX-1 (RatLaps) concentrations being significantly lower in immunized, icariin treated mice than in immunized, vehicle treated (p<0.01) and non-immunized (p<0.005) mice. Icariin also reduced the clinical signs of arthritis. Icariin inhibited cathpesin K activity in vitro and was effective in a mouse model of CIA similar to human RA, suggesting that this agent may have promise in the treatment of patients with RA.
    Phytomedicine: international journal of phytotherapy and phytopharmacology 06/2013; 20(11). DOI:10.1016/j.phymed.2013.04.019 · 3.13 Impact Factor
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