Is Taurolidine a candidate for treatment of rheumatoid arthritis?
OBJECTIVE
To study the therapeutic potential of taurolidine (TRD), a derivative of taurine with known anti-inflammatory and anti-proliferative properties, in various experimental models of synovitis.


METHODS
In vitro: fibroblast-like synoviocytes (RA FLS) isolated from the synovial tissue of patients with rheumatoid arthritis (RA) were cultured in the presence of either TRD or polyvinylpyrrolidine (PVP), the pharmaceutical stabilizer of TRD, which was used as a control. Proliferation of RA FLS and cytokine (IL-6 and IL-8) release were measured. In vivo: (A). The effect of systemic TRD treatment on the development of collagen-induced arthritis (CIA) in female DBA1/J mice was investigated. Mice were treated either with intraperitoneal injections of 1 ml of 2% Taurolin Boehringer Ingelheim (TRD +PVP) or with PVP as placebo. The incidence of arthritis, myeloperoxidase (MPO) activity in periarticular tissue, as well as serum concentration of IgG specific to collagen II (IgG alphaCII) were determined. (B). The effect of intra-articular TRD treatment was studied in rabbits with antigen-induced monoarthritis (AIA). After the induction of AIA of right knees rabbits were treated either with intra-articular injections of 0.5 ml of 2% Taurolin or 0.5ml PVP ( placebo). The animals were examined for clinical signs of arthritis and diameter of joints was measured. After termination of the experiment, the arthritic knees were examined and histopathology of the joints was assessed. In addition, serum amyloid A (SAA) concentration was measured.


RESULTS
n vitro: TRD exerted cytotoxic effect on RA FLS when applied at concentrations >100 microM. TRD at non-cytotoxic concentrations, inhibited PDGF-triggered RA FLS proliferation, reduced IL-1beta - stimulated production of IL-6 and slightly decreased intracellular content of IL-8. In vivo: (A). Intraperitoneal treatment with Taurolin significantly reduced the incidence (30%) of CIA when compared to the control mice (79%). However, Taurolin failed to control the development of CIA in mice with high serum level of IgG alphaCII (>1000 U).(B). Intra-articular application of 2% Taurolin resulted in amelioration of AIA in all treated rabbits (reduced diameter of arthritic joints and smaller rise of SAA level as compared to the control animals). Histopathologic evaluation revealed pannus formation in both groups and extensive necrotic lesions of synovial tissue treated with TRD, suggesting synoviorthesis-like effect.


CONCLUSIONS
Results from AIA and from in vitro RA FLS studies suggest that intra-articular administration of TRD could be used as a "pharmacological scalpel" to remove the inflamed synovium. Our data confirmed anti-inflammatory and anti-proliferative properties of TRD in all experimental models encouraging further studies which should evaluate its therapeutic potential in RA.
Marcinkiewicz
J
J
Department of Immunology, Jagiellonian University Medical College, Cracow, Poland. mmmarcin@cyf-kr.edu.pl
Głuszko
P
P
Kontny
E
E
Kwaśny-Krochin
B
B
Bobek
M
M
Wierzchowski
W
W
Ciszek
M
M
Maśliński
W
W
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D010047:Ovalbumin; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013829:Thiadiazines / Q000494:pharmacology / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007074:Immunoglobulin G; D013829:Thiadiazines; D013654:Taurine; C012566:taurolidine; D010047:Ovalbumin; D003094:Collagen; D009195:Peroxidase