Background Despite methotrexate (MTX) is widely used as the first choice in the treatment of rheumatoid arthritis (RA), there is no universally accepted method of the optimal schedule for dose initiation and escalation. The higher starting dosage and faster increasing schedule is considered to be associated with higher efficacy, because it is expected to achieve steady state concentrations of intracellular MTX polyglutamates (MTX-Glu) more quickly. In contrast, in Japan, the officially approved dosage of MTX for RA treatment had been fixed up to 8mg/wk from 1996 to 2011, whereas the maximum doses of 20 to 30mg/wk were commonly used in the rest of world. As a result, we have very unique experience of extra-low-dose MTX (ExLD-MTX) treatment for RA.
Objectives To evaluate the efficacy of ExLD-MTX treatment for RA; and to investigate the concentrations of intracellular MTX-Glu after ExLD-MTX treatment.
Methods RA cases treated with ExLD-MTX (n=133) were retrospectively investigated. After 12 months of the treatment, the rates of achieving remission criteria and of withdrawing from the initial treatment were calculated. If dose escalation of MTX above 10mg/wk was required due to insufficient efficacy, the case was count as withdrawal. In order to compare the results with the MTX monotherapy arm in PREMIER study, the remission criteria was defined as DAS28 of <2.6. Next, the concentrations of MTXGlu1-7 in red blood cell (RBC) lysates after ExLD-MTX treatmentwere quantitated with using HPLC method.
Results After 12 months of ExLD-MTX treatment (mean MTX dosage: 6.13±0.69 mg/wk), 72.2% of cases were still maintained with the same treatment. The remission criteria for DAS28 (<2.6) were achieved 31.4% of patients. The efficacy seems to be comparable to those of MTX monotherapy arm (mean MTX dosage: 16.9mg/wk) in PREMIER study, i.e. the maintenance rate for the initial treatment was 75.7% and the remission rate was 21.0%. The backgrounds of the patients were similar in both studies. The rates of withdrawal because of adverse events and of insufficient efficacy were 2.2% and 25.6% in ExLD-MTX group, while 7.4% and 17.9% in MTX monotherapy arm in PREMIER study. The analysis of intracellular MTX-Glu after ExLD-MTX treatment revealed distinct distribution of MTX-Glu subtypes, i.e., 88.2±19.5% of MTX-Glu was MTX-Glu6-7, whereas the rate of MTX-Glu6-7 was reported to be less than 1% after usual MTX treatments.
Conclusions Although higher starting dosage and faster increasing schedule for MTX is considered to be better, we found that the efficacy of ExLD-MTX treatment is comparable to usual MTX treatments. As the longer-chain MTX-Glu is reported more important in the clinical response compared with the shorter-chain, the intensive distribution in MTX-Glu6-7 subtypes after ExLD-MTX treatment may be an explanation for the efficacy. Furthermore, since MTX exposure was known to induce up-regulation of folylpolyglutamate hydrolase, which removes glutamic acid from MTX-Glu, ExLD-MTX treatment could be favorable for accumulation of the longer-chain MTX-Glu. On the other hand, reaching high doses of MTX in a short period may be required to achieve the steady state concentrations of MTX-Glu more quickly. The optimal schedule for dose initiation and escalation of MTX may need a re-evaluation.
Disclosure of Interest None Declared