Is hirudin a potential therapeutic agent for arthritis?

Is hirudin a potential therapeutic agent for arthritis?

Author: K Scott,    School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand,  k.scott@auckland.ac.nz

A recent pilot study by Michalsen et al showed that a single brief treatment with medicinal leeches (Hirudo medicinalis) can give relatively long term relief from pain in osteoarthritic joints. A number of leech salivary components are known,  which may contribute to this effect.¹ Although there was no evidence for any therapeutic outcomes, other than pain relief, the extended timescale suggests that   one or more leech components may exert more than an anaesthetic or analgesic effect. Independent evidence indicates that the  leech anticoagulant protein, hirudin, may make a significant contribution to this phenomenon.

A synovial stimulatory protein (SSP), acting as an autoantigen to which T lymphocytes from patients with rheumatoid arthritis  respond, has been identified in synovial fluid.² A smaller protein, derived from human fibroblasts, and identifiable from its amino acid sequence as a fragment of the SSP, has been found to bind to a hirudin-agarose affinity chromatography matrix.³ More recently, we have shown that both the SSP and its smaller derivative, now known as the DING protein, are found in synovial fluid samples and synovial fibroblasts from normal subjects, and from patients with a range of arthritic conditions, includin  rheumatoid and osteoarthritis. The proteins act as autocrine growth stimulators for normal and arthritic synovial fibroblasts.⁴ The presence of hirudin can inhibit this stimulation.³ Given that hyperproliferation of synovial fibroblasts is believed to contribute to the formation of the destructive pannus   that is characteristic of some arthritic joints,⁵ the SSP and DING protein may act to promote this process, and hirudin may have the potential to retard it. Hirudin might   thus have value in treating arthritis. Recombinant hirudin has already been used in a range of therapeutic anticoagulant applications,^6–8 so patient safety and other clinical data have been collected and evaluated. A trial of hirudin in an antiarthritis role  may now be appropriate.

The first DING protein isolates displayed proteolytic activity, and its inhibition was believed to be the basis of the action  of hirudin, but subsequent DING preparations have had little or no proteolytic activity.^3,4 The basis of the inhibitory action of hirudin is thus not known. Peptides derived from hirudin such as hirulog (bivalirudin),   which are effective anticoagulants by virtue of thrombin inhibition,^9,10 may not possess the ability to bind and inhibit the SSP or DING proteins.