Drug delivery technology predicted to allow safer and more effective use of steroids in the treatment of rheumatoid arthritis
SummaryAn estimated 5 million individuals suffer from rheumatoid arthritis. Corticosteroids are the most dramatically effective short-term anti-inflammatory drugs; however, clinical benefit for rheumatoid arthritis often diminishes with time. Because of their long-term systemic side effects, corticosteroids are usually given only after a careful and prolonged trial of less hazardous drugs. Liposomes are artificial vesicles efficiently phagocytosed by macrophages and recent advances such as the developm
Rheumatoid arthritis is one of the more common autoimmune diseases along with multiple sclerosis, type I diabetes and Crohn’s disease. Approximately one in five people in the western world suffer from autoimmune diseases and some estimates indicate that 75% of these are women. In total it is predicted that the annual value of the market for drugs used to treat autoimmune disease will soon exceed $20 billion. An estimated 5 million individuals suffer from rheumatoid arthritis, a figure which will increase to 5.7 million by 2010 (for further information on the rheumatoid arthritis market click here).
Corticosteroids are the most dramatically effective short-term anti-inflammatory drugs; however, their clinical benefit for rheumatoid arthritis often diminishes with time. Corticosteroids do not predictably prevent the progression of joint destruction, although a recent report suggested that they might slow erosions. Furthermore, severe rebound follows the withdrawal of corticosteroids in active disease. Because of their long-term systemic side effects, corticosteroids are usually given only after a careful and prolonged trial of less hazardous drugs.
Future directions for the development of rheumatoid arthritis therapeutics are ever focusing on disease modifying drug classes ('s Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates is recommended for readers requiring a full overview of DMARDs click here). An alternate strategy however is the utilization of evolving drug delivery technology to target classic therapeutics such as the steroids to arthritic joints.
One area of drug delivery technology that has advanced greatly in recent years involves the incorporation of therapeutic agents into liposomes, artificial vesicles that are composed of phospholipid bilayers (for a full evaluation of emerging drug delivery technology click here). One particular feature of liposomes is that they are efficiently phagocytosed by macrophages and can hence be targeted towards inflamed tissue such as the synovium in rheumatoid arthritis. One problem with this technology is that the liposomes are also taken up in the liver and the spleen reducing synovial exposure. This hurdle has been overcome by coating liposomes with poly(ethylene)glycol (PEG) reducing their recognition and removal by the mononuclear phagocyte system within these organs. Using PEG coated liposomes Metselaar et al were able to target prednisolone to the inflamed joints of rats with adjuvant arthritis greatly improving the therapeutic activity of this corticosteroid. Improved efficacy is thought to result from steroid actions on macrophages and furthermore since steroids are membrane permeant, once inside the macrophages they can diffuse out to other cells within the synovium of inflamed joints and hence macrophages represent a conduit for drug action.
In their April Annals of the Rheumatic Diseases article (access this article here) Metselaar et al advance the data presented from their rat study, investigating the effect of liposomal targeting on the efficacy of glucocorticoids in a murine model of collagen-induced arthritis. This model differs from the adjuvant model and joint erosion is a particular feature of collagen-induced arthritis.
In a cooperation between the department of Rheumatology and Advanced Therapeutics in Nijmegen and the Utrecht Institute of Pharmaceutical Sciences, they investigated the effect of investigated the effect of a single intravenous treatment with prednisolone encapsulated in long-circulating PEG-liposomes on both joint inflammation and cartilage destruction and investigated the phenomenon of selective homing of these liposomes in the inflamed synovium.
Mice with collagen type II-induced arthritis were intravenously treated with liposomal and free prednisolone phosphate following the onset of disease (treatment was started when the severity of disease was about 50% that of the maximum level attained in control animals and thus represents a therapeutic rather than a preventative intervention). Treatment with 10 mg/kg liposomal prednisolone phosphate resulted in a strong and lasting resolution of joint inflammation. 10 mg/kg free prednisolone phosphate only became slightly effective after repeated daily injections. Although joint inflammation recurred 1 week after treatment with liposomal prednisolone phosphate, knee joint sections prepared at this time indicated that the cartilage damage was still reduced. Histochemical evaluation revealed that liposomes concentrated in the synovial lining of diseased joints while unaffected joints did not take up liposomes.
This important study suggests that liposomal technology may target steroid to inflamed joints resulting in fewer administrations to produce greater efficacy with reduced side-effects in patients with rheumatoid arthritis.
Source: TherapeuticAdvances, June, 2004
(see also a second editorial in this edition of TherapeuticAdvances, "Novartis’/Schering’s VEGF receptor tyrosine kinase inhibitor, PTK787/ZK222584 as a candidate treatment of rheumatoid arthritis" - click here)