Methotrexate therapy in asthma increases T cell susceptibility to corticosteroid inhibition.
BACKGROUND
Concomitant methotrexate (MTX) therapy of severe, oral corticosteroid-dependent asthmatics has been shown to be corticosteroid sparing, but the mechanism is unknown. We hypothesized that MTX therapy of these patients increases the susceptibility of their T cells to corticosteroid inhibition.


OBJECTIVE
To measure prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells from a group of these patients before, during and following MTX therapy.


METHODS
Eighteen severe asthmatics (median (range) age 56 (33-68) years, FEV1 61 (38-69)% predicted, dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high-dose, inhaled corticosteroids) were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. After 12 weeks of MTX, oral prednisolone dosages were reduced systematically over 16 weeks, provided that asthma control did not deteriorate. Patients were followed for a further 12 weeks after MTX withdrawal. Concentration-dependent, prednisolone inhibition of lectin-induced proliferation of peripheral blood T cells was measured just prior to MTX therapy (week 1) and at weeks 12, 28 and 40, and IC50 concentrations were interpolated.


RESULTS
By week 28 of MTX therapy, patients were able to reduce oral prednisolone dosages from (median, SIQR) 15 (10-20.5) to 5.9 (1.4-9.4) mg/day (P<0.01) without alteration of lung function and symptoms, while median IC50 values for prednisolone inhibition of peripheral blood T cell proliferation were reduced from 49 (21-144) to 4 (1-9) nm (P<0.0001). These increased again to 15 (9.4-25.7) mg/day and 36 (18-67) nm, respectively, following MTX withdrawal. A correlation (P<0.01) was observed between percentage reductions in prednisolone dosages in vivo and fold changes in prednisolone IC50in vitro between weeks 12 and 28.


CONCLUSIONS
This effect of MTX may at least partly account for its oral corticosteroid-sparing effect in severe asthma.
Corrigan
C J
CJ
Guy's, King's and St Thomas' Imperial College Schools of Medicine, London, UK. chris.corrigan@kcl.ac.uk
Shiner
R
R
Shakur
B H
BH
Ind
P W
PW
D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D010835:Phytohemagglutinins / Q000276:immunology; D011239:Prednisolone / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D010835:Phytohemagglutinins; D011239:Prednisolone; D008727:Methotrexate