In people at high risk of rheumatoid arthritis, an antibody directed against immune cells, B lymphocytes, significantly delays the onset of clinical signs of the disease. A first step for its prevention and a clear improvement in the understanding of the disease.
In a placebo-controlled study, a single infusion of 1000 mg of an anti-CD20 antibody (rituximab), directed against the immune cells responsible for producing the antibodies (B lymphocytes), delayed the first clinical signs of rheumatoid arthritis, and therefore the disease itself.
In addition to providing a preventive treatment for rheumatoid disease, this well-conducted study provides evidence in favor of the major role of B lymphocytes in the onset of rheumatoid arthritis (pathogenic role).
There is therefore a preclinical phase of general autoimmune disorder which corroborates the idea that rheumatoid arthritis could begin elsewhere than in the joint. This study was published Annals of the Rheumatic Diseases.
A good quality study
The Dutch and Swedish researchers tested the benefit of a B lymphocyte reduction in people at high risk of developing rheumatoid arthritis with autoantibodies (rheumatoid factor or anti-citrullinated peptide antibodies or ACPA), but without clinical signs of the disease (preclinical phase). These were 81 people with no signs of inflammatory arthritis but with arthralgia and both anti-citrullinated peptide antibodies and rheumatoid factor.
They were randomly selected to be included in a randomized, double-blind study testing either a single infusion of 1000 mg of rituximab or a placebo. They were then followed for an average of 29 months, during which time 30 people developed arthritis (37%).
Very significant results
At 12 months of follow-up, the risk of developing polyarthritis in the placebo group is 40%, and it is therefore clearly a population at risk. Above all, it is reduced by 55% (HR 0.45; 95% CI: 0.154 to 1.322) in the group treated with anti-CD20 antibodies. Treatment with rituximab is therefore at the origin of a delay of 12 months in the development of polyarthritis compared to placebo (p <0.0001).
A high sedimentation rate and the presence of anti-α-enolase peptide 1 citrullinated antibodies at the start of the study would be predictive factors for the subsequent development of arthritis.
A preclinical stage of RA
Previous studies have shown that rheumatoid factor (RF) and anti-citrullinated peptide (ACPA) antibodies may be present in the blood of some people more than 10 years before they develop rheumatoid arthritis with autoantibodies.
The research that led to the recognition of this phase of general (systemic) autoimmunity not only supported the idea that the process leading to disease might not be initiated in the joints, but that a directed action at this time and specifically against B lymphocytes could delay the onset of the disease or even stop it.
The role of the B lymphocyte
Previous rheumatoid arthritis prevention studies have used broad-spectrum drugs or corticosteroids with relatively little success. In this study, the treatment was directed specifically against B lymphocytes (anti-CD20 antibodies).
It demonstrates that B cells therefore play a crucial role in the process of triggering the disease but, in addition to their involvement in the production of immunoglobulins, in particular rheumatoid factor and ACPA, B cells are cells which are also capable of present the possible disease-causing antigen to other immune cells to amplify the process. They can thus also activate T lymphocyte cells by costimulation and also produce a variety of cytokines.
window of opportunity
A single infusion of rituximab causes a marked decrease in the level of B lymphocytes for several months, then their level generally rises in the blood after a year. Thus, in the context of the curative treatment of rheumatoid arthritis, treatment with rituximab at a higher dose is renewed on average after one year.
In recent years, effective treatments have been put in place increasingly early in the disease because, in addition to protecting the joints against bone damage, this early treatment seems able to modify the immunity and the evolutionary course of the disease. : we speak of a “window of opportunity”.
With this study, we are entering a new era, that of the “preventive window of opportunity”, a period when it would theoretically be possible to prevent rheumatoid disease, for several months, or even for life.
In practice
It is not a question of testing everyone for specific antibodies for rheumatoid arthritis and then treating everyone who has these antibodies with rituximab, 1000 milligrams every 12 months. Indeed, only 40% of people positive for the 2 antibodies declared the disease after 12 months of follow-up.
On the other hand, it is possible to define scores making it possible to define the people in whom to look for these antibodies and, in the event of positivity, to define another score (integrating the high sedimentation rate and serology α-enolase peptide 1 citrullinated) to even to determine which are the ones that will actually make the disease to treat them, with an anti-CD20 antibody or more likely another less aggressive and more specific treatment for auto-reactive B lymphocytes. Studies are already underway.
In the end, polyarthritis is a generalized autoimmune disease that begins elsewhere than in the joints and for which preventive treatment is now possible if it is also directed against B lymphocytes.
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