Infliximab (Remicade™)
Osteoprotegerin (OPG)
Interleukin-1 Receptor Antagonist
PEGylated sTNF-RI

Tg197 mice are transgenic mice that overproduce tumor necrosis factor-a(TNF-a) and, as a result, develop a progressive polyarthritis. They die before 20 wks of age presumably because of the cachexia induced by TNFa. The objective of this study was to determine the therapeutic potential of an anti-TNFaantibody in this mouse model. Mice were treated biweekly with intraperitoneal saline OR 3 mg/kg OR 10 mg/kg of anti-TNFa(infliximab) as soon as the pups were weaned (4 weeks). In addition, mice of 7-8 weeks of age who had > 2 paws with an arthritis score of > 2 were treated in a similar manner.

Results: 1) In the 4 week pup groups, infliximab treated animals gained significantly more weight and had lower arthritis scores than the saline-treated controls. There was a dose dependent effect in that the 10 mg/kg dose performed more effectively than the 3 mg/kg dose. 2) In the 7-8 week pup groups, there was an increase in body weight in the infliximab treated animals while saline treated pups failed to thrive and went on to death. Infliximab treated pups also had lower arthritis scores and, on histological analysis, they demonstrated decreased pannus, decreased synovitis and decreased bone erosion compared to saline treated controls. Since the growth plate of the pups does not close, healing of erosions could also be evaluated and, in fact, was observed in the infliximab treated group.

Editorial Comment: : There were no surprises in this study but the results are, nontheless, encouraging. Healing of erosions has been suggested as a possibility in human RA patients treated with infliximab, but there are currently no criteria for defining erosion healing in humans. This animal model reminds us of the important role TNF has in mediating cachexia.

OPG is a member of the TNF receptor superfamily and inhibits osteoclast differentiation. The objective of this study was to determine if OPG (.016, 0.6, or 1 mg/kg daily, sc) could prevent bone damage in rat mycobacteria-induced adjuvant arthritis (AdA) compared to arthritic and normal controls. OPG therapy was begun following the onset of clinical signs of arthritis on day 9 as evidenced by paw swelling and ambulatory difficulties, and continued to day 16. Inflammation and erosion score, bone mineral density (BMD), histopathology and osteoclast number were evaluated.

Results:

These data show that daily administration of OPG treatment prevents bone damage in AdA in a dose dependent fashion evidenced by a 75% reduction in bone erosion and osteoclast number. In contrast, no resolution of inflammation if observed with OPG treatment.

Editorial Comment: It has been suggested that patients with RA may sometimes exhibit improvement on x-rays, but not much relief of clinical symptoms, in response to treatment. This interesting study identifies a mechanism (OPG inhibition of osteoclast differentiation) by which this might occur. OPG might be a useful adjunctive therapy for RA.

Using a rat mycobacteria-induced adjuvant arthritis (AdA) model, patterns of bone protection were evaluated following treatment with ILםra, PEG sTNF–RI, or OPG. Inoculation of mycobacteria was on day 0, therapy was initiated on day 9, and inflammation and erosions were assessed on day 16.

Results:

IL-1ra, PEG sTNF-RI, and OPG reduced bone damage in a dose dependent fashion. Some bone sparing with little reduction in inflammation was evident with high doses of IL-1ra and PEG sTNF-RI alone, while combination therapy caused significant reductions erosion scores that correlated with the degree of inflammation in the bone marrow and soft tissues. In contrast, OPG therapy resulted in significant skeletal sparing that was completely independent of inflammation.

These data suggest that joint destruction caused by arthritis may be better managed by a therapy that combines an anti-inflammatory agent (IL-1ra or PEG-sTNF-RI) with an anti-erosive protein (OPG).

Editorial Comments: see comment for preceding abstract (POS-353)

(see above)

The objective of this study was to determine if combination therapy with IL-1ra and sTNF-RI produced greater clinical benefit than therapy with either agent alone. Using the type II collagen and adjuvant arthritis models in rats, doses of IL-1ra (100 and 20 mg/kg sc daily) and PEG sTNF-RI (3, 1, & 0.3 mg/ml ip on days 1, 3 & 5) were administered alone and in combination beginning with the onset of clinical signs of arthritis evidenced by ankle joint swelling. Normal and vehicle control treated rats were included.

Results:
Established Type II Collagen Arthritis Model Combination therapy with IL-1ra 100 mg/kg and sTNF-RI (all dose) resulted in additive beneficial clinical effect whereas combination therapy with IL-1ra 20 mg047;kg and sTNF-RI (all dose) resulted in greater than additive beneficial effect with the outcome for both combination therapies being good to excellent amelioration of the clinical signs of arthritis. A statistically significant benefit was also observed on body weight change.

Developing Adjuvant Arthritis Model Efficacy evaluations utilized 100 mg/kg of IL-1ra and 3 or 1 mg/ml sTNF-RI. Both combinations produced additive to greater than additive effects for all outcomes measured. Body weight changes were not significant, although significant weight changes were observed in the spleen and liver.

Blood levels in rats given 20 mg/kg IL-1ra are similar to blood levels in humans dosed daily at 1-2 mg/kg (current clinical trial dosing).

Editorial comment: Approximately 30% of RA patients do not respond to TNF inhibitors. IL-1 has inflammatory properties similar to TNF; therefore, inhibition of IL-1 is a rational clinical approach. These animal studies support the rationale for a combined approach.

(see above)

(see above)

All information contained within the Johns Hopkins Arthritis Center website is intended for educational purposes only. Physicians and other health care professionals are encouraged to consult other sources and confirm the information contained within this site. Consumers should never disregard medical advice or delay in seeking it because of something they may have read on this website.

Copyright © 1998-2000. The Johns Hopkins University on behalf of its Division of Rheumatology. All rights reserved.