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Reprinted from Medical Sciences Bulletin Published by Pharmaceutical Information Associates, LTD
Rheumatoid arthritis (RA) is a common and often debilitating disease characterized by the inflammation of synovial membranes, leading to deterioration of joint cartilage and bone. Since RA is associated with human lymphocyte antigen DR4 (HLA-DR4), the disease is thought to be autoimmune in origin. Type II collagen is probably the autoantigen involved in RA, since it is the most abundant structural protein in cartilage and since immunizing animals with this protein induces an arthritis ressembling RA. Therapy includes steroids, nonsteroidal anti-inflammatory agents, and immunosuppressants, which are associated with significant toxicity and only partially control symptoms. Recently a Harvard Medical School team reported that oral tolerization (desensitization) is an effective and nontoxic technique for suppressing the symptoms of RA
Oral tolerization involves feeding the patient the antigen thought to be involved in the autoimmune attack. It takes advantage of the fact that a foreign protein entering the body via the digestive tract apparently suppresses the immune response to that protein, rather than triggering it. A number of groups have studied oral tolerization in animals to suppress autoimmune diseases resembling certain human diseases, including human sclerosis (MS) uveitis, and diabetes, as well as RA. In one clinical trial involving 30 MS patients, the oral administration of bovine myelin antigens decreased the number of T cells that reacted with myelin basic protein, the autoantigen in MS.
In the first Harvard trial, Trentham et al. administered very small doses of solubilized Type II collagen to 10 patients with refractory RA. After discontinuing immunosuppressive and disease-modifying drugs (methotrexate, mercaptopurine, azathioprine, or auranofin), patients were given 0.1 mg of collagen daily for 1 month, and then 0.5 mg for the next 2 months. The dosage was chosen on the basis of animal studies. Clinical response was defined as a 50% or greater improvement in the number of swollen and tender joints, accompanied by a 50% or greater increase in two additional measures (morning stiffness, 15-meter walking time, grip strength, Westergren erythrocyte sedimentation rate, or physician or patient global assessment), lasting for at least 2 months after the treatment period. Six of the 10 patients showed substancial clinical response, and one showed a complete response (disease remission) lasting 26 months. There were no adverse effects.
On the basis of results of this phase I trial, a 90-day, double-blind, phase II trial was conducted involving 60 patients with severe, active RA. Patients received either placebo or solubilized Type II collagen (1.0 mg for 1 month, then 0.5 mg for 2 months). At the study's end, 59 of the 60 patients were evaluable : 28 had received collagen, and 31 placebo. Compared with the placebo group, the collagen group showed significant improvements in joint swelling, tenderness or pain (as well as in indices of swelling or tenderness) and in 15-meter walking time at months 1, 2, and 3. During the period when patients were off immunosupressants, those receiving collagen showed stability or improvement, while those in the placebo group tended to deteriorate (with the exception of four patients who showed a substancial placebo effect). Four patients in the collagen group showed complete resolution of disease, while none of the placebo patients showed remission. No side effects or laboratory effects were seen (including rheumatoid factor and antibodies to Type II collagen).
Feeding Type II collagen to RA patients may alter T cell function, either by causing T cell anergy or by triggering the production of suppressor T cell that migrate to joints and block T cell-mediated inflammation. A longer multicenter trial is needed, which would include a washout period and 6 months of treatment. ``If longer term efficacy is established`` said the investigators, ``oral collagen would be a preferable treatment because it is not toxic.`` The Harvard trials were sponsored AutoImmune, a Lexington, MA biotechnology company founded in 1988 to commercialize oral tolerization. (Trentham DE et al. Science. 1993; 261 1727-1730. Barinaga M. Science. 1993; 261 : 1669-1670.)
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