Why Certain Patients Don’t Respond to Steroids: One Possible Explanation
- CD4+CD25int T Cells in Inflammatory Diseases Refractory to Treatment with Glucocorticoids
- The Journal of Immunology, Volume 179, Number 11, December 1, 2007, pp. 7941-7948
What is the topic?
Steroid medications are often prescribed for people with lupus or other autoimmune diseases such as rheumatoid arthritis. Although steroids have many undesirable side effects, they work quickly and very well to control lupus. However, for a small percentage of lupus patients, steroids don’t provide relief; these patients are said to be "steroid resistant" (SR), and must take other medicines, most of which are not as rapidly active, to treat their disease flares.
What did the researchers hope to learn?
The researchers in this study wanted to see if they could find out what makes people steroid resistant. In particular, they were interested in learning about the immune cells of SR individuals, to see how they might be different from the immune cells of people for whom steroids are effective. They performed a study in patients with ulcerative colitis, so it is important to understand that the results may or may not be relevant to lupus patients who are steroid resistant.
Previous studies had shown that steroids slow down the reproduction of certain kinds of immune cells called CD4+ T cells. By limiting the number of these cells, steroids help reduce inflammation and other signs of autoimmune disease. But not all CD4+ T cells are the same. Some CD4+ T cells produce large amounts of a protein called CD25; these cells are called CD4+CD25high; others produce none, so they are called CD4+CD25- ("negative"). In between these two extremes is a group that produces an intermediate amount, and those cells are called CD4+CD25int.
Who was studied?
The researchers obtained blood samples from 23 healthy individuals and 6 patients with ulcerative colitis who had a history of steroid resistance. All of the people in the study were Caucasian, and men outnumbered women by 2 to 1 in both the healthy group and the SR patients.
How was the study conducted?
Blood samples were taken, and the blood was processed so that the researchers had collections of immune cells to work with. They treated these immune cells with chemical techniques so they would show up under a microscope, and so that it could be determined how much CD25 they had. They also measured how many times the cells divided, which is a measure for their reproduction (more dividing cells are seen in inflammatory states). They then exposed these cells to different doses of a steroid medicine called dexamethasone to see which kinds of cells responded and which did not, and compared the responses from the cells of the healthy individuals and the SR ulcerative colitis patients.
What did the researchers find?
Very weak doses of dexamethasone had little effect on the reproduction of either the CD4+CD25- T cells or the CD4+CD25int T cells, both of which continued to divide and multiply at the same rate that was seen without any steroids. However, as the researchers increased the doses of dexamethasone to the levels usually given to treat patients, the two different kinds of T-cells responded quite differently. Reproduction of the CD4+CD25- T cells slowed down considerably and was even more limited as the dose was further increased. The CD4+CD25int T cells did not appear to be affected by the dexamethasone and continued to divide and create more cells regardless of the dose of the steroid.
When comparing the two groups from whom the samples were obtained, the researchers noted that the percentage of CD4+CD25int T cells was much higher in the SR ulcerative colitis patients than in the healthy subjects. There were some healthy subjects (17%) whose T cells also showed high steroid resistance, which led the researchers to conclude that steroid resistance was not necessarily a function of the disease, but a characteristic of the individual person whether or not they were ill. This may be a benign factor until a person has an illness that would benefit from steroid treatment.
What were the limitations of the study?
This study was conducted not on lupus patients, but rather on ulcerative colitis patients, which is a different autoimmune disease entirely. These findings may or may not apply to people with lupus who do not respond to treatment, but would certainly be worth studying in lupus patients. Also, the study participants were all Caucasian. This is both an asset and a detriment to the study. It is an asset because ethnic differences in normal steroid responsiveness would not confuse the picture as much (of course all Caucasians are not alike as proven by this study). It is a detriment because it is not yet possible to apply the results to people from other genetic backgrounds. Also, in this study men outnumbered women, which is precisely the opposite of what occurs in lupus. Another limitation is the fact that the researchers focused only on the T cell populations, which are only a minority of immune cells. Though their findings did seem to indicate a role for CD4+CD25int T cells in promoting steroid resistance, there could still be other factors involved that also contribute.
What do the results mean for you?
Although their number is small, lupus patients who do not respond to steroid medicines face a number of challenges. Steroids are one of the most immediately effective treatments for lupus flares, despite the fact that they have distressing side effects. So although most patients (and their doctors) prefer to avoid steroids, they are often extremely effective in moderate to severe flares and can even be life-saving.
Against that background, this study holds out a possible way for doctors to use blood tests to identify which of their lupus patients may or may not respond as well to steroids, which might lead to more aggressive dosing in emergencies or earlier introduction of other strong immune suppressants. In addition, if researchers can know for sure which factors contribute to steroid resistance, there is the possibility that treatments can be developed to overcome those problems. For those reasons, this study offers hope that more sophisticated approaches can be developed in the future to provide safer and more effective (and individualized) treatments.