Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
A Proof of Concept Trial of Gleevec (Imatinib) in Active Diffuse Scleroderma (DSSc)
Pope1, Janet, McBain2, Donna L., Petrlich1, Lisa, Watson1, Sharon, Bender1, Louise, Deleon3, Faye, Summers4, Kelly
There has been interest in tyrosine kinase inhibitors in systemic sclerosis (SSc) due to the effects on PDGF, TGFbeta, adhesion molecules and other factors.
We performed a 6 months proof of concept double blinded RCT of imatinib in active diffuse SSc with skin biopsies using 2mm biopsy on abdomen at time 0 and repeated beside original biopsy at 6 months; and plasma (0,3,6 months) analyzing PDGF, RANTES, E-Selectin, VCAM-1, ICAM-1, MMP-9, tPAI-1, IFN-gamma, IL-1alpha, IL-1beta, IL-4, 6, 10, 12p70, 13, 17; MCP-1,3, MIPs, CD40L, VEGF, TNFalpha, and TGFbeta, and patient and physician outcomes including HAQ, and modified Rodnan skin score (mRSS). We used 4:1 randomization and planned to enroll 20 patients, stratifying by presence or absence of stable background Methotrexate use. Novartis supplied imatinib and placebo for this investigator initiated study.
After enrolling 10 patients mean age (9 active and one placebo);7 Female, mean age 51, 3.1 years disease duration (0.5 to 6 years) and mRSS skin score: 32 (SD 8), 3 had tendon friction rubs, patient global 66 (on 100 mm VAS), MD global 46, and HAQ 1.7; we found poor tolerability and high AEs (5 had to stop due to AEs or interrupting dose including fluid retention, weakness, nausea, vomiting, chest pain, worsening anemia, and hair loss), only 4 patients completed the 6 months on study drug at recommended dose. There was also one SAE (active drug marked fluid retention) so we stopped enrolling further subjects. Using ITT analysis, at 6 months, we found: no difference in any parameter with all p values (none were near significance) including: skin score (6 months mRSS 30. P=0.6), CRP, ESR, MD global (36) and patient global (39), HAQ (1.5), tissue (skin biopsy) and plasma cytokines and other factors. The 6 months health transition was rated by two who dropped out as much worse, and one more as much worse, another worse, 4 the same and 2 better. The plasma and tissue cytokines in those on active treatment were not statistically different from 0 to 6 months except sVCAM-1(plasma p<0.001) and sICAM-1 (tissue p=0.009).
In relatively early active disuse SSc, imatinib was not well tolerated and did not change any clinical or skin biopsy parameters over 6 months. It is unlikely that imatinib will be a feasible treatment for early SSc with respect to modifying skin sclerosis or inflammation.
To cite this abstract, please use the following information:
Pope, Janet, McBain, Donna L., Petrlich, Lisa, Watson, Sharon, Bender, Louise, Deleon, Faye, et al; A Proof of Concept Trial of Gleevec (Imatinib) in Active Diffuse Scleroderma (DSSc) [abstract]. Arthritis Rheum 2009;60 Suppl 10 :608