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Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 1999 Jun;58(6):342–349. doi: 10.1136/ard.58.6.342

Intra-articular primatised anti-CD4: efficacy in resistant rheumatoid knees. A study of combined arthroscopy, magnetic resonance imaging, and histology

D Veale 1, R Reece 1, W Parsons 1, A Radjenovic 1, P O'Connor 1, C Orgles 1, E Berry 1, J Ridgway 1, U Mason 1, A Boylston 1, W Gibbon 1, P Emery 1
PMCID: PMC1752895  PMID: 10340958

Abstract

OBJECTIVES—CD4+ T cells sustain the chronic synovial inflammatory response in rheumatoid arthritis (RA). SB-210396/CE 9.1 is an anti-CD4 monoclonal antibody that has documented efficacy in RA when given intravenously. This study aimed to establish the safety and efficacy of the intra-articular administration of SB-210396/CE 9.1 compared with placebo, examining its mode of action using a combined imaging approach of arthroscopy, magnetic resonance imaging (MRI), and histology.
METHODS—Thirteen RA patients with active, resistant knee synovitis, were randomised to intra-articular injection of placebo (n=3), 0.4 mg (n=3) or 40 mg (n=7) of anti-CD4 after sequential dynamic gadolinium enhanced MRI, followed by same day arthroscopy and synovial membrane biopsy. Imaging and arthroscopic synovial membrane sampling were repeated at six weeks. This study used a unique region of interest (ROI) analysis mapping the MRI area analysed to the specific biopsy site identified arthroscopically, thus providing data for all three modalities at the same synovial membrane site.
RESULTS—12 patients completed the study (one placebo treated patient refused further MRI). Arthroscopic improvement was observed in 0 of 2 placebo patients but in 10 of 10 patients receiving active drug (>20% in 6 of 10). Improvement in MRI was consistently observed in all patients of the 40 mg group but not in the other two groups. A reduction in SM CD4+ score was noted in the 40 mg group and in the 0.4 mg group. Strong correlations both before and after treatment, were identified between the three imaging modalities. Intra-articular delivery of SB-210396/CE 9.1 was well tolerated.
CONCLUSIONS—SB-210396/CE 9.1 is safe when administered by intra-articular injection. A trend toward efficacy was found by coordinated MRI, arthroscopic, and histological imaging, not seen in the placebo group. The value of ROI analysis was demonstrated.



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Figure 1  .

Figure 1  

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Magnetic resonance image of the knee joint. This demonstrates a typical dynamic T1 weighted gradient echo magnetic resonance image (TR/TE/flip angle 30/12/60° ) used to map with the computer localised regions of interest (area=11.8 mm2) at the suprapatellar pouch (SPP) and the tibiofemoral joint (TFJ).

Figure 2  .

Figure 2  

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The percentage change of median dynamic enhanced (Gadolinium-DTPA) magnetic resonance imaging parameters over baseline with respect to: (A) maximum rate of normalised signal intensity enhancement (MRE) reflecting synovial capillary permeability; and (B) the maximum normalised signal intensity enhancement (ME) reflecting the perfusion and the volume of the extracellular fluid at the regions of interest and globally in the three treatment groups. (A) Deterioration in MRE is seen at both regions and globally in the placebo group. Ten per cent improvement is seen only at the tibiofemoral joint region in the 0.4 mg group. Improvement (up to 10%) is seen at both regions of interest and globally in the group treated with 40 mg of active drug. (B) Deterioration is seen at the suprapatellar region and globally in the placebo group. Mild improvement (<10%) is seen at the tibiofemoral joint region and globally in the 0.4 mg group. Improvement (10-20%) is seen at both regions of interest and globally in the group treated with 40 mg of active drug.

Figure 3  .

Figure 3  

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Quantitative maps of gadolinium-DTPA magnetic resonance images of the knee joint pre- and post-treatment with SB-210396. The images show the difference in maximal rate of signal intensity enhancement (sec-1 ) before and after treatment of one patient from the 40 mg treatment group. The scale ranges from minimum = 0.016 (red) to maximum = 0.88 (yellow). The pre-treatment image is predominantly yellow indicating a high maximal rate of enhancement while in contrast, the post-treatment image shows more red reflecting a reduced rate of enhancement . 

Figure 4  .

Figure 4  

Figure 4  

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Photomicrographs of the synovial membrane before and after treatment. Immunoperoxidase staining with an anti-CD4 monoclonal antibody (OKT4), of a patient who received 40 mg active drug. (A) Synovial tissue before treatment shows staining of numerous CD4 + cells. (B) Synovial tissue after treatment from the same patient showing marked reduction of CD4+ cells.          

Figure 5  .

Figure 5  

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Percentage change in the median CD4 scores. This graph shows change from baseline in immunohistological CD4 scores at the regions of interest and globally, for the three treatment groups. Improvement (>30%) was seen at all sites in the 40 mg group. Improvement was also seen at the tibiofemoral joint region in the 0.4 mg group and at the suprapatellar region in the placebo group.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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