Structural effects of intra-articular TGF-β1 in moderate to advanced knee osteoarthritis: MRI-based assessment in a randomized controlled trial

Abstract

Background: To determine effects of allogeneic human chondrocytes expressing TGF-β1 (TG-C) on structural progression of MRI features of knee osteoarthritis over a 1 year period.

Methods: This phase II randomized controlled trial of TG-C included patients with moderate to advanced osteoarthritis. Patients were randomized to receive an intraarticular 3:1 mixture of non-transduced allogeneic human chondrocytes and TG-C or placebo. 3 T MRI was acquired for all patients at baseline and follow-up (3, 6 and 12 months). MRIs were assessed using the WORMS system including cartilage damage, bone marrow lesions (BMLs), meniscal damage/extrusion, Hoffa-, effusion-synovitis, and osteophytes. Analyses were performed on a whole knee level, compartmental level, and subregional level. Binary logistic regression with Generalized Estimating Equation was used to compare risks of progression, adjusting for baseline age and gender. Mann - Whitney - Wilcoxon tests were used to assess differences for continuous variables.

Results: Fifty-seven Patients were included in the TG-C group and 29 in the placebo group. At 12 months, knees in the TG-C group showed less progression of cartilage damage compared to placebo on a whole knee level (34.6% vs. 47.9%; adjusted RR 0.7, 95%CI [0.5-1.1], p = 0.077). Less progression of Hoffa-synovitis and effusion-synovitis was observed in the TG-C group compared to placebo (9.6% vs. 21.1%, adjusted RR 0.5, 95%CI [0.2,1.2], p = 0.115). No statistically significant differences were seen for BMLs, meniscal damage and osteophytes.

Conclusions: Intraarticular treatment with TG-C showed fewer patients in the treated group with progression in structural OA features and other MRI-defined inflammatory markers such as Hoffa-synovitis and effusion-synovitis. However, no differences were observed in regard to progression of BMLs and meniscal damage, or hypertrophic osteophyte formation.

Trial registration: NCT01221441 .Registered 13th October, 2010.

Keywords: MRI; Osteoarthritis; Randomized controlled trial; Tgf-β1.

Conflict of interest statement

Ethics approval and consent to participate

Patients provided written informed consent after the nature of the study was fully explained and understood by the patient. For site 1 (Investigator Dr. Mont, Sinai Hospital of Baltimore) it was The LifeBridge Health, Inc. Institutional Review Board. Committee reference number 1627. For site 2 (Investigator Dr. Romness, Commonwealth Orthopedics) it was Schulman Associates IRB, Inc. Committee reference number 09–8354-0. For site 3 (Investigator Dr. Cherry, University Orthopedics Center) it was Western Institutional Review Board. Reference number 1122564. For site 4 (Investigator Dr. Bramlet, Advent Research) it was Schulman Associates IRB, Inc. Committee reference number 201102669. For site 5 (Investigator Dr. Parvizi, The Rothman Institute) it was the Thomas Jefferson University Institutional Review Board. Committee reference number 2405. Ethical approval was obtained from all of the above named committees.

Consent for publication

Not applicable

Competing interests

AG received consulting fees from TissueGene, AstraZeneca, Merck Serono, GE Healthcare, Pfizer, SanofiAventis and OrthoTrophix. He is the President of Boston Imaging Core Lab (BICL), LLC. FWR is the CMO of BICL and received consulting fees from Merck Serono and National Institute of Health. MDC is a shareholder of BICL. GK, OC, MN and AO are employees of TissueGene, Inc. JN has nothing to disclose.

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Figures

Fig. 1

Sagittal intermediate-weighted fat suppressed MRI in treated patient at baseline (a), 3 months (b) and 6 months (c) follow up show improvement of cartilage focal defect of the posterior medial femoral condyle with almost perfect filling at 6 months (long arrows). Also note the grade 1 BML at the central weight-bearing medial femoral condyle disappears at 3 months (a, short arrows). There is a Hoffa-synovitis grade 1 and moderate size tibial osteophytes. There is a femoral intrachondral osteophyte that seems to be slightly increasing in size (dotted arrows)

Fig. 2

Axial intermediate-weighted fat-suppressed MRI in treated patient at baseline (a) and 12 months (b) follow up show improvement of cartilage focal defect and thickness of the medial patella (long arrows). Also note the decrease in volume of the joint effusion (small arrows)

Fig. 3

Coronal intermediate-weighted fat-suppressed MRI in treated patient at baseline (a) and 3 months (b) follow up show no improvement of cartilage damage in the medial tibiofemoral compartment (WORMS grade 6 at central medial femur; WORMS grade 5 at central medial tibia). There is a medial meniscal maceration/extrusion (arrow). There is a slight improvement of the subchondral bone marrow lesion/cysts at the central medial tibia (small arrows) and slight worsening of the subchondral bone marrow lesion/cysts at the central medial femur (long arrows). Note large medial osteophytes