LUPUS FOUNDATION OF AMERICA - An Early Study of a New Treatment (Tocilizumab) for Lupus

An Early Study of a New Treatment (Tocilizumab) for Lupus

Tocilizumab in systemic lupus erythematosus: Data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study.
Authors: Illei GG, Shirota Y, Yarboro CH, Daruwalla J, Tackey E, Takada K, Fleisher T, Balow JE, and Lipsky PE. (2010).
Arthritis & Rheumatism 62: 542-552.

What is the topic?
Interleukin-6 (IL-6) is a protein that helps to control inflammation in the body. Lupus patients sometimes have increased IL-6 in the blood, and some studies suggest that IL-6 might go up with lupus flares. If the activity of IL-6 could be blocked, it might help to decrease inflammation.

The drug studied here, tocilizumab, is a "humanized" monoclonal antibody (meaning that it is designed to resemble natural antibodies that people make, which are proteins in the immune system that can recognize and block other proteins). Tocilizumab recognizes and binds to IL-6 receptors, which are proteins that IL-6 signals to in order to induce inflammation. By blocking the ability of IL-6 to signal to its receptor, it is hoped that this can reduce the effects of IL-6 in the body.

What did the researchers hope to learn?
The researchers wanted to find out if treatment with tocilizumab might be safe and effective to treat lupus. However, this was only a preliminary study, sort of like dipping your toe in to make sure that a larger study is a good idea. No firm conclusions can be made from the results of a preliminary study (often called a Phase I study), but if all goes well in this early study, it can give the researchers more confidence to pursue more studies.

Who was studied?
16 adults (mostly women) with moderately active lupus were recruited to participate in the study at the National Institutes of Health Clinical Center in Bethesda, MD. Each patient had to have some evidence of lupus inflammation in the blood. Patients were required to use a form of contraception during the study. Patients could not be taking any antibody treatments, experimental therapies, or high doses of prednisone.

How was the study conducted?
Patients were assigned to receive one of the following doses of tocilizumab in a vein (IV): 2 mg/kg, 4 mg/kg, or 8 mg/kg. Mg/kg means the number of milligrams of the drug for every kilogram of body weight; so a heavier person could get a higher total dose than a lighter person, but would be receiving the same amount based on their weight. The drug was given to each patient once every two weeks over a 12-week period, for a total of seven treatments.

Assessments of lupus disease activity were made every two weeks for twelve weeks and then again during a six-week follow-up period. The following measures of lupus activity were studied in the blood: the total amount of antibodies (called "immunoglobulins"), inflammatory proteins called "complement," and antibodies to double-stranded DNA and cardiolipin, which are common in people with lupus.

What did the researchers find?
As a result of treatment with tocilizumab, lupus disease activity showed an improvement in about half the patients and no patients experienced flares during the study period. Most patients with arthritis had some improvement in their joints.

Patients showed an increase in blood levels of two proteins called "albumin" and "hemoglobin," which suggested decreased inflammation. Overall, patients had decreased levels of a specialized white blood cell called a "plasma cell" that makes antibodies; this result was noticed during the second half of treatment and during the follow-up period. Patients also showed less activation of inflammatory proteins (decreased complement) in the blood that was related to increasing doses of tocilizumab.

Patients taking tocilizumab showed a moderate decrease in levels of some kinds of antibodies (called IgG) and a decrease in antibodies to double-stranded DNA, which are often seen in lupus. Levels of antibodies to cardiolipin, another common antibody seen in lupus, did not change with drug treatment.

Infusions were generally well-tolerated, and all patients developed at least one mild side effect. One patient had a serious case of "stomach flu"-like symptoms, but recovered and completed the study. Three additional patients (all from the highest dose group) had significant decreases in their white blood cells, one of whom withdrew from the study. Most patients had at least one infection, most of which were treated with antibiotics or antiviral drugs, and all of these patients completed the study.

What were the limitations of the study?
This was only a preliminary study with very few patients and a short study period. By splitting the few patients in the study between three dosing groups, each group was extremely small, so it is hard to draw conclusions about what might be the best dose (although there was more decrease in the white blood cells called neutrophils in the highest dose group). This study did not include a group of patients who did not get any tocilizumab, and both the doctors and patients knew what medication was being given. Therefore, no conclusions can be drawn from an early study like this about whether this treatment is safe or effective for lupus in the long term.

What do the results mean for you?
The results of this study suggest that tocilizumab might have some effects on lupus inflammation, but the large number of infections would suggest that maybe smaller doses should be tried next. The goal of new treatments is to moderate the immune system, and the goal of early studies like these is to try and figure out the optimal way to give a treatment like this in the next, larger study.