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Why Certain Patients Don’t Respond to Steroids: One Possible Explanation Monday, March 17, 2008 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. source Labels: Glucocorticoids, Inflammatory Diseases, research, steroid
~~~ Are Increased Levels of Nitric Oxide a Sign of Kidney Damage in Lupus? What is the topic? Lupus disease activity often occurs without any apparent signs or symptoms. This is especially true when lupus affects the kidneys, which is known as lupus nephritis. It is possible for lupus to cause significant kidney damage even before a patient is diagnosed. However, though there may be no visible symptoms, there are chemical changes occurring in the cells and tissues that can be measured. Therefore, a major emphasis among lupus researchers is to find simple laboratory tests can be used to detect otherwise silent lupus disease activity. A laboratory test that can be used in this way is called a biomarker. One potential biomarker that is being investigated is nitric oxide (chemical symbol, NO), since NO is one of the chemicals involved in the body’s immune response. What did the researchers hope to learn? The researchers wanted to see if there was any relation between the level of NO and lupus, and if increased levels of NO were related to lupus nephritis. Who was studied? Eighty-three adult lupus patients and 40 healthy people of similar age and background were recruited for this study. Ninety five percent (95%) of the lupus patients were women; 80% were African American; both percentages were higher than those in the healthy group. The researchers divided the 83 lupus patients into three groups: (1) lupus patients with no history of nephritis; (2) lupus patients with history of nephritis but no active kidney disease; and (3) lupus patients with active kidney disease that required a biopsy (a biopsy involves removing tissue from the kidney and studying it with a microscope and with other special laboratory techniques). Among the 83 lupus patients, 49 either had a history of nephritis or had active nephritis over the course of the study. How was the study conducted? At their first visit, all of the patients had blood samples taken, and these blood samples were tested for levels of nitrates and nitrites, which are indications of nitric oxide production; together the nitrates and nitrites are called NOx. The researchers compared the NOx levels of the lupus patients and the controls. They also did further comparisons of the lupus patients’ NOx levels with other standard laboratory measures used to evaluate lupus, such as the presence of certain antibodies and other immune system agents (called complement) in the blood, or protein in the urine. The lupus patients had regularly scheduled visits every 3 months for at least one year (some were seen for as long as two years). During those visits further blood tests were taken to measure NOx levels at that time, and other tests conducted to evaluate their lupus disease. Patients who had signs of active lupus nephritis had biopsies of their kidneys. Since both smoking tobacco and certain foods can raise the blood levels of NOx, participants in the study agreed not to smoke and to eat only a low-NOx diet 24 hours before each visit. What did the researchers find? As expected, the researchers found that the blood levels of NOx in the lupus patients were significantly higher than those without lupus at the first visit. Furthermore, among the lupus patients, those with active lupus nephritis had higher levels than in the other groups. Also, higher levels of NOx were associated with several of the standard laboratory measurements for lupus, including elevated levels of protein in blood and urine (which are signs of kidney disease) and lowered complement, especially the C3 form of complement. Over time, higher NOx levels were associated with greater lupus disease activity. Turning their attention to the group of patients who had undergone a biopsy for active lupus nephritis, the researchers found that the patients with the highest level of NOx also had the most serious degree of kidney damage. They also looked at how the patients with kidney disease responded to medical treatment; those patients who did not get better (“non-responders”) had higher levels of NOx than those who did respond. There are two reasons why a chemical can be increased in the bloodstream: either the body is making increased amounts, or the body is not efficiently eliminating the chemical which is being made. The researchers did another series of tests to make sure that the NOx levels were a result of higher production and not because the kidneys were less able to remove the NOx compounds from the blood. Those tests showed that it was, indeed, increased production and this appeared to be related to the activity of C3 complement. All of these findings led the researchers to conclude that elevated levels of NOx in the blood could be a potential useful marker for lupus disease activity. They also suggested that any medication that aimed to prevent kidney damage in lupus patients might have to limit the production of NO. However, just because something is a marker for disease activity does not necessarily mean that all effective treatments would have to eliminate it. If NO is triggering something else that damages the kidney, then a treatment aimed at that second thing might be effective for nephritis regardless of the NO level. What were the limitations of the study? The size of the study group -- 83 lupus patients -- was small, especially considering how different the inflammation of lupus can be from one person to the next. Also, nearly 80% of the lupus patients in the study were African Americans; that is a good aspect of the study, since people of African descent may have worse kidney involvement and have previously not been studied well enough. However this does limit the ability to draw conclusions about people with lupus who might be from different genetic backgrounds. There are also some limitations to the measurements used. As the researchers themselves pointed out, lupus activity rises and falls over time, and measurements taken at three-month intervals really may not capture important information during the intervening months. Of less concern, but something that should be noted, the researchers didn’t really measure the levels of NO itself, but used the blood levels of nitrate plus nitrite as indicators of NO production. This measurement seems to be useful, but much more could be learned about the specific chemical changes that are going on and in what way they may impact the kidney. What do the results mean for you? A number of previous studies had pointed to increased NO production as an important factor in lupus, but those studies were "after the fact"; they only looked back at the records of lupus patients to see if there were any associations. This was the first study to examine the relationship going forward, following lupus patients over time, and gathering information about NO levels in the course of their treatment and evaluation. Thus, it adds strength to the notion that NO may be a useful biomarker for lupus disease activity that could help doctors know what is going on when their patients may not have obvious symptoms. Their suggestion that limiting NO production might be important to consider for new medications for lupus nephritis is also very intriguing. Both of these points -- the value of NOx as a biomarker and its role as a target for new medications -- are definitely worthy of further studies. source Labels: kidney, lupus neprithis, Nitric Oxide, research
~~~ A potential therapy for lupus nephritis when other medications fail Saturday, September 01, 2007 From Arthritis & Rheumatism, April 2007Lupus nephritis (kidney disease) is a serious complication of lupus. Researchers in Sweden tested to see if providing rituximab (Rituxan) in combination with cyclophosphamide (CYC) would be a safe and effective therapy for lupus nephritis patients who had previously not responded to CYC. The researchers found that rituximab, in combination with CYC, was effective in treating lupus nephritis in patients who had previously not responded to CYC. Read more > Labels: CYC, kidney, lupus neprithis, research, rituximab
~~~ Results of a preliminary study of rituximab for difficult NPSLE From the Annals of the Rheumatic Diseases, April 2007 Lupus may affect the central nervous system (NPSLE), with estimates varying widely (from 12% to 75%) for the number of lupus patients who experience minor or moderate flares in the nervous system. Researchers from Japan found that the cancer drug rituximab was effective in treating the NPSLE symptoms in a small group of 10 patients. Read more Labels: nervous system, NPSLE, research
~~~ Novel antibodies as markers for lupus activity in the nervous system Novel antibodies as markers for lupus activity in the nervous system From the Annals of the Rheumatic Diseases, April 2007' Diagnosing lupus can be difficult because the symptoms are sometimes similar to those of other conditions. Researchers hoped to learn if antineuronal antibodies (anti-Ns) could be used to diagnose central nervous system involvement in lupus (NPSLE). After looking at blood samples from 198 people, patients who had been diagnosed with lupus had higher levels of anti-Ns in their blood samples than was seen in other study participants. Read more > Labels: nervous system, novel, research
~~~ Lupus and HPV Lupus and HPV From Arthritis & Rheumatism. May 2007 Previous studies have suggested that women with lupus may not be able to produce an effective immune response to HPV. Researchers wanted to determine whether lupus patients are at enhanced risk of HPV infections. In this study of 112 women, researchers found that the women with lupus had a very high rate of infection with a particular sub-type of HPV-16, and those lupus patients who had large amounts of this virus had a higher rate of abnormal cervical smears. Read more >
~~~ Anti-Sm antibodies and lupus disease activity may be important in predicting outcomes Anti-Sm antibodies and lupus disease activity may be important in predicting outcomes From Lupus, March 2007 It is still not possible to predict in advance who will develop lupus and, what course each patient's disease may take. The researchers hoped to sort through several of the probable contributing factors that could help predict the progression and severity of disease activity among lupus patients.Researchers in Canada studied the records of 330 patients from three different racial and ethnic groups who were diagnosed with lupus in Manitoba, Canada, over a period spanning more than 20 years and noted a number of differences among the three ethnic groups. Read more >
~~~ At risk for thrombosis: FXII autoantibodies and the antiphospholipid syndrome At risk for thrombosis: FXII autoantibodies and the antiphospholipid syndrome From the Annals of the Rheumatic Diseases, April 2007 People with lupus who have antiphospholipid antibodies (aPL) are at risk for blood clots, including heart attacks, strokes, clots in the legs, lungs, or other organs, and pregnancy complications. Researchers for this study of 127 patients found antibodies to Factor XII (FXII), a protein that plays a role in preventing blood clots, were present in 40% of the lupus patients as opposed to only 7% of the healthy people. Read more > Labels: research, thrombosis
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