Background/Purpose:

Methotrexate (MTX) and leflunomide are categorized
as DMARDs of first choice in treating rheumatoid arthritis patients. MTX should
be used cautiously in patients with impaired kidney function, but treatment
with MTX may also show an increased effectiveness in these patients, because of
accumulation. If MTX is contraindicated, for instance because of more severely
impaired kidney function, leflunomide can be used without dose adjustment. We
aimed to explore the role of the kidney function for the 6 month treatment
response to either methotrexate or leflunomide in RA patients.

 Methods:

We
selected patients from a longitudinal RA database, who started MTX monotherapy
or leflunomide treatment and had clinical follow ups over at least 6 months. In
a multivariable regression analyses, we used change in the simplified disease
activity index (SDAI) after 6 months as dependent variable, and baseline SDAI,  creatinine (or glomerular filtration rate),
and MTX dose as independent variables.

Results:

We
identified 256 patients starting MTX (80% female, 59% rheumatoid factor, RF,
positive; mean±SD:
SDAI: 17.2±12, creatinine:
0.83±0.14 mg/dl, glomerular filtration rate (GFR): 83±22 ml/min, end MTX dose:
20.6±6.1) and as comparator group 80
patients starting a treatment of at least 6 months with leflunomide (86%
female, 57% RF positive, mean±SD SDAI: 13.6±8.8, creatinine:0.85±0.23,
GFR: 88±53).

Regression analyses in the
MTX cohort showed that that, after adjusting for MTX dose, higher creatinine
was associated with higher SDAI response after 6 months of treatment (p=0.029).
Analogously, in a separate analysis lower GFR was also significantly associated
with larger clinical improvement (p=0.04) (Figure).
SDAI response in patients with impaired kidney function and lower MTX dose
(GFR <75ml/min and <20mg of MTX, respectively) was similar to patients with
normal kidney function and higher MTX dose (GFR >75ml/min and ≥25mg of
MTX). In patients treated with leflunomide,
creatinine as well as GFR were not associated with SDAI change after 6 months
of treatment (p=0.585, p=0.962, respectively).

Figure: Regression
splines for SDAI response at 6 months of MTX treatment (blue with confidence
intervals) and leflunomide (red dotted with CI) predicted by glomerular
filtration rate

Conclusion:

We demonstrated here that patients with impaired renal
function seem to benefit in terms of SDAI response during treatment with
methotrexate. This was not found in patients treated with leflunomide. Higher
treatment responses in patients with impaired kidney function indicate
increased clinical benefit. This could also indicate room for higher MTX doses,
which are historically limited to 25mg/week, in patients with normal kidney
function and accompanied folate substitution.