Objective
Low-dose methotrexate (MTX), a mainstay in the therapy of rheumatoid arthritis, is effective in only 60–70% of patients, a finding mirrored by poor anti-inflammatory efficacy in some animal models, most notably collagen-induced arthritis. To determine whether genetic factors or the model itself were responsible for the poor response to MTX we directly compared the responses of four inbred mouse strains to MTX in the air pouch model of acute inflammation.
Methods
Exudate leukocyte count and adenosine concentration were determined in inbred mice treated with methotrexate (0.75 mg/kg intraperitoneally [IP] every week for 4 weeks) or vehicle 4 hours after injection of carrageenan into the air pouch using previously described methods(
Results
MTX significantly reduced the exudate leukocyte count in C57BL/6 and BALB/c, but not DBA/1 (the strain used in the collagen arthritis model) or DBA/2 mice. In a parallel fashion MTX increased adenosine concentration in inflammatory exudates of C57BL/6 and BALB/c, but not DBA/1 or DBA/2 mice. Anti-inflammatory and adenosine responses to MTX in DBA1xC57BL/6 F1 and F2 offspring were most consistent with single genetic loci being responsible for each phenotype.
Conclusion
Genetic factors contribute to the anti-inflammatory efficacy of methotrexate and a single locus involved in methotrexate-induced adenosine upregulation is likely responsible for the observed resistance to MTX in DBA/1 mice.