*5.2. Genetic Variants A*ff*ecting csDMARD E*ff*ectiveness*

Methotrexate-sensitivity pharmacogenetic studies are quite numerous as it is the first-line therapy drug of choice. The main genetic variants associated with methotrexate treatment response determined by separate original works, multicenter studies, and meta-analyses are summarised in Table 2; similar loci associated with the effectiveness of targeted DMARD therapy are also shown. A better methotrexate response is noted in the presence of 3435C > T polymorphism's T-allele in *ABCB1* gene exon 26. In contrast, del28-bp TSER\*3/\*3 homozygotes of the thymidyl synthase gene (*TYMS*) require a higher dose of the drug. Finally, a C > G substitution at position 347 of the *ATIC* gene is associated with methotrexate toxicity. As a less often used first-line drug for RA treatment, leflunomide has a lower response rate among 19AA homozygotes of the *DHODH* gene, encoding an enzyme of the de novo pyrimidine synthesis chain [67]. According to recent meta-analyses and earlier original works, sensitivity to methotrexate is associated with 34C/T substitutions in the *AMPD1* gene, 675T/C in the *ATIC* gene, and 80G/A in the *SLC19A1* gene in Caucasians, while 3435C/T in the *ABCB1* gene in this population and 28-bp 2R/3R in the *TYMS* gene in representatives of other races are associated with resistance. Polymorphisms in the *MTHFR* (C677T and A1298C) and *TYMS* (1494 del6 and 28-bp 2R/3R) genes were associated with the severity of side effects in various populations [11,68–70]. The *FPGS* gene encoding the transfer protein has rs10987742 and rs10106 SNPs associated with methotrexate sensitivity in RA [71]. Among the genes encoding other transfer proteins, methotrexate resistance in RA was associated with the *SLC22A11* gene (rs11231809, T-allele), the *ABCC1* gene (rs246240, G-allele; rs3784864, G-allele), and its CGG-(rs35592, rs2074087 and rs3784864) and CGG-haplotypes (rs35592, rs246240 and rs3784864), as well as with substitutions in the *SLC19A1*, *SLC46A1*, and *SLCO1B1* genes [72,73]. However, the last two mentioned studies were performed in a Portuguese population only and may not reflect associations in other Caucasoid groups. It is preferable to focus on meta-analyses that include dozens of original works with Caucasians as an object of study. Thus, the association of the methotrexate toxicity and 80G/A polymorphism in the *RFC1* gene, encoding a transfer protein involved in the folate cycle, was shown [11,74].


**Table 2.** Polymorphisms (non-HLA genes) associated with disease-modifying antirheumatic drugs (DMARD) efficacy, according to meta-analyses and multicenter studies data.

MTX—methotrexate, IL6 – interleukine 6, TNF—tumor necrosis factor.

Patients could also be prescribed transitional therapy with glucocorticoids, anti-inflammatory drugs that suppress the immune system (prednisone, dexamethasone, methylprednisolone), before the maximum effect of DMARDs is reached. Subsequently, corticoid dose is gradually reduced, and the therapy is transferred completely to DMARDs. The rs37972 polymorphism minor allele of the glucocorticoid-induced transcript 1 gene (*GLCCI1*) was shown to be associated with reduced glucocorticoid sensitivity in men [82]. Polymorphisms associated with these anti-inflammatory drug sensitivity panels include the GLCCI1-C allele, glucocorticoid receptor gene (*GR*) BclI-G (rs41423247) and N363S-G (rs6195) alleles, and the G2677A/T replacement in the multidrug resistance factor (MDR1) *ABCB1* gene [82,87].
