Methotrexate: Implications of pharmacogenetics in the treatment of patients with Rheumatoid Arthritis.

BACKGROUND: Methotrexate (MTX) is an anti-folate drug with anti-proliferative and anti-inflammatory effects. MTX proved to be the most highly effective, fast-acting disease modifying anti-rheumatic drug (DMARD), being widely used for the treatment of rheumatoid arthritis (RA). This review aims to describe the main genetic variants identified concerning proteins that play a role in methotrexate's kinetics and efficiency profile. METHODS: A literature review was conducted since January of 2000 until December 2020, by searching the PubMed and Embase bibliographic databases, employing the following MeSH terms: methotrexate, pharmacogenetics, pharmacokinetics, and rheumatoid arthritis. The search was limited to articles in English language. Two independent reviewers screened the titles and abstracts followed by a full-text review to assess papers regarding their eligibility. A total of 48 articles matched the research criteria and were analyzed. RESULTS: Reduced folate carrier 1 (RFC1), a constitutively expressed folate transport protein that has high affinity for MTX is responsible, almost exclusively, for the transport of folate and MTX into the cell. The most studied variant of the gene is the 80G>A variant, mapped within exon 2, on chromosome 21. It seems to improve RA responses to MTX, clinical efficacy with long disease remission. ABC transporters are involved in the efflux of MTX from cells. An increased expression and function of these transporters should decrease MTX concentrations in target cells, resulting in lack of therapeutic response. ABCB1 3435 C/T is a high frequency polymorphism, significantly associated with RA good responses, symptom remission and reduced adverse events, due to MTX treatment. Thymidylate synthase (TYMS) is involved in thymidine synthesis. MTX decreases TYMS activity by inhibition and decreasing the access to tetrahydrofolate (THF) cofactors. The most common genetic variant of the TYMS gene consists of a 28 bp tandem repeat, with double and triple number of repeats (2R and 3R). The 3R allele genotype was associated with decreased efficacy and increased toxicity. The 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme is indirectly inhibited by MTX. The most common SNPs of the MTHFR gene are C677T and A1298C. Both are associated with a decreased efficacy and an increased toxicity of MTX. CONCLUSION: MTX response is affected by many gene variants; the effect of each variant separately is likely to be small. Additionally, gene-gene interaction seems to enhance the potential role of linkage disequilibrium. This shows the emerging need for a better gene characterization and to improve the knowledge about variants distribution according to ethnicity, to explain different responses to MTX at an individual level.

Biobanks for aging research - perceptions and choices among rheumatology outpatients.

OBJECTIVE: Biobanks for research (BBR) have enormous value for research, including those specifically oriented to chronic diseases. Knowing public attitudes and perceptions is key to design and implement patient-centered BBR. We assessed patient awareness, perception and choices among rheumatology outpatients regarding aging biobanking activities. METHODS: We conducted a cross-sectional survey of patients, aged 50 or older, attending an outpatient rheumatology tertiary department. Demographic data and perceptions about biobanking were collected and statistical analysis was performed. RESULTS: 132 valid questionnaires were obtained (mean age: 63,4; 68,2% female; mean education years: 8,35). 61,7% of respondents did not know the specific term "biobank", 57,7% knew they could donate biological material for BBR, 89,9% agreed with these infrastructures and 88,3% would consider participation Those participants with more years of education were more knowledgeable and prone to biobank participation. Willingness to participate in BBR was mainly related (86,4%) to the advancement of scientific knowledge and not individual gain. Scientific research institutes were indicated as the most adequate institutions to manage BBR. Informed consent, anonymity and confidentiality ranked as top requisites for biobank participation. 61,3% of respondents expressed their agreement with aging biobanks, considering these as a sign of respect for specific problems of people of older ages such as higher disease burdens. CONCLUSION: Knowledge of biobanks was found to be limited. Participants were positive toward the setting up of biobanks in general and patient-centered aging biobanks in particular. Knowledge about biobanks and acceptance were higher among participants with higher education years.

The Portuguese Society of Rheumatology position paper on the use of biosimilars - 2017 update.

Biosimilars are new and more affordable similar versions of previously approved reference biological drugs. Following the approval of the first monoclonal antibody biosimilar in 2013, the Portuguese Society of Rheumatology issued a position paper on the use of biosimilars in rheumatic conditions covering efficacy, safety, extrapolation, interchangeability, substitution and pharmacovigilance. However, as this is a rapidly evolving field, it was felt that the knowledge and evidence gathered since then justified an update of these statements. Literature searches on these issues were performed and the search results were presented and discussed in a national meeting. Portuguese rheumatologists considered that affordability should be taken into consideration when initiating a biological drug, but other factors were equally important. In patients already on reference biological treatment, switch to a more affordable biosimilar is desirable, provided a set of conditions is rigorously met. Automatic substitution is not acceptable and current evidence is insufficient to support interchangeability. Extrapolation of clinical indications is endorsed by Portuguese rheumatologists, and the statements on safety, pharmacovigilance and traceability are in accordance with the previous position paper.

[Cystic Rheumatoid Arthritis--case report]. / Artrite Reumatoide Quística--a propósito de um caso clínico.

Among the many radiological findings seen in Rheumatoid Arthritis RA small subchondral geodes and erosions are typical. Large geodes are far less common abnormalities and their presence may indicate diagnostic and therapeutic difficulties. We present a case report of a 55-year old woman with seronegative RA that developed a large geode in the knee with extensive joint destruction.