New folate antagonists selectively target pathway important in rheumatoid arthritis

Methotrexate (MTX), a folate antagonist that blocks folic acid activity, is the most widely used disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis.

It enters the cell via several pathways, one of which involves folate receptor â (FRâ), which is highly specific for cells present in the joints of patients with rheumatoid arthritis (RA). During the last two decades, a second generation of folate antagonists has been designed to address some of the limitations of MTX, which include adverse side effects and resistance. A new study examined the capacity of several of these new drugs to determine whether they could selectively target cells that express FRâ. The study was published in the January issue of Arthritis & Rheumatism (

Led by Gerrit Jansen of the VU University Medical Center in Amsterdam, researchers analyzed FRâ expression from biopsy samples from the knee joints of RA patients before and after four months of treatment with MTX and from controls. These experiments confirmed that FRâ expression is highly specific to activated macrophages (a type of immune cell that plays a role in the inflammatory response in RA) in the synovial membrane of RA patients.

The researchers went on to examine new folate antagonists to determine which ones would most likely be beneficial in treating synovial inflammation. Several of these agents showed a markedly higher binding affinity for FRâ compared to MTX, which has a high affinity for entering cells via another pathway known as reduced folate carrier (RFC). This pathway is found throughout the body, however, and is therefore not specific for synovial cells. Researchers also examined whether two of the newer drugs would inhibit growth of FRâ-expressing cells and found that one of them, BCG 945, accomplished this at low concentrations. Interestingly, the uptake of BCG 945 was inhibited by the addition of folic acid. "In this context, it may be anticipated that, for example, fortification of food with folate may reduce the activity of this folate antagonist, whereas restriction in dietary folate intake could further enhance the therapeutic efficacy of these types of drugs," the authors state. BGC 945 was originally discovered at the Institute of Cancer Research in London, and is now known as ONX 0801. Onyx Pharmaceuticals has an exclusive worldwide license to this compound.

They note that although MTX is the drug of first choice in the treatment of RA, its efficacy can be improved. "Further evaluation of folate antagonists with properties of high binding affinity for FRâ and low affinity for the RFC may pave the road for a more selective targeted therapy of activated synovial macrophages," they conclude.

In an accompanying editorial in the same issue, Christoph Fiehn of the Center for Rheumatic Diseases in Germany notes that folate antagonists remain the key to RA treatment, both now and in the future. "Antifolate drugs that, unlike MTX, are FRâ-specific would have a stronger effect on synovial macrophages and a weaker effect on other types of cells that take up MTX by the ubiquitously expressed RFC," he explains. "A higher therapeutic effect and a lower rate of side effects of FRâ-specific antifolates as compared with MTX could possibly be the result."


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