Session Type: Abstract Submissions (ACR)
Background/Purpose: A number of trials have shown that adding MTX benefits some, but not all, biologics and small molecules to treat RA. Specifically, though treatment of RA with an anti-TNF+MTX has been shown to be more beneficial than with the biologic alone,1-3 the same was not consistently observed with tocilizumab (TCZ)+MTX.4,5 Thus, it remains a challenge to determine whether cotreatment with MTX is a better option for patients. We have previously reported that BioMAP activities detected with TCZ alone were highly similar to those of TCZ+MTX, whereas the effects of adalimumab (ADA) alone differed from those of ADA+MTX.6 Here we evaluate whether MTX alters the pattern of BioMAP activities of tofacitinib (TOF) in order to predict whether the effects of this drug can be modulated by cotreatment with MTX.
Methods: Human primary cell–based BioMAP disease models7,8 were used to generate phenotypic activity profiles for compounds alone and in combination with MTX at concentrations that cover their clinical Cmax ranges9-11: TCZ, 200 mg/mL; TOF1, 1.1 mM; TOF2, 0.12 µM; MTX, 10 mM. Agents and combinations were tested under standard7 and soluble interukin-6 receptor–stimulated conditions. Changes in protein-based, clinically relevant end points (biomarkers)7 and proliferation were evaluated by t-test and other statistical methods to determine whether activities of the combinations differed from those of the individual agents.
Results: Several activities detected with TOF1+MTX or TOF2+MTX were statistically significantly different (p<0.01) from those of TOF1 or TOF2 profiled alone. Cytokine and chemokine levels (M-CSF, G-CSF), inflammation markers (VCAM-1, E-selectin, and IP-10), and tissue-remodeling activities (thrombomodulin and PAI-1) were all modulated differently by TOF+MTX vs TOF alone. In contrast, the profile of TCZ+MTX was not significantly different from that of TCZ alone, with only MTX-mediated antiproliferative effects on endothelial cells (3C) and B cells (BT) contributing to the pattern of TCZ activities.
Conclusion: These data show that though TCZ has diverse effects on inflammatory responses, cotreatment with MTX elicits few additional activities and does not impact TCZ effects. In contrast, TOF+MTX impacts immune function, inflammation markers, and matrix-remodeling end points in human primary cell disease models differently than does TOF or MTX alone. The pharmacodynamic interactions between TCZ and MTX in BioMAP are significantly less pronounced than those between TOF and MTX. These data are consistent with the comparable efficacy of TCZ in monotherapy and combination therapy seen in some clinical trials4,5 and in real life12 and suggest that TOF could be more beneficial in combination with MTX.
References: 1. Arthritis Rheum. 2006;54:26-37. 2. Lancet. 2004;28:363:675-681. 3. Ann Rheum Dis. 2010;69:964-975. 4. Ann Rheum Dis. 2013;72:43-50. 5. EULAR 2014;SAT0257. 6. EULAR 2014;THU0526. 7. Drug Discov Today. 2014;19:113-125. 8. J Biomol Screen. 2013;18:1260-1269. 9. Expert Rev Clin Pharmacol. 2013;6:123-137. 10. Drugs R D. 2010;10:271-284. 11. Mod Rheumatol. 2005;15:405-409. 12. Ann Rheum Dis. 2012;71:1950-1954.
DiscoveRx Corp (BioSeek division),
E. L. Berg,
M. R. John,
E. H. Choy,
Abbott Laboratories, Boehringer Ingelheim, Chelsea Therapeutics, Chugai Pharma, Ferring Pharmaceuticals, GSK, Jazz Pharmaceuticals, MSD, Novartis, Pierre Fabre Medicament, Novimmune, Roche, UCB,
Abbott Laboratories, Allergan, AstraZeneca, BMS, Boehringer Ingelheim, Chelsea Therapeutics, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmacuetical, GSK, ISIS, Jazz Pharmaceuticals, MedImmune, Merrimack Pharmaceutical, MSD, Novimmune, Novartis, ,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/methotrexate-impacts-the-effects-of-tofacitinib-but-not-tocilizumab-on-clinically-relevant-biomarkers-in-human-primary-cell-based-biomap-disease-models-can-we-utilize-in-vitro-models/