Apr. 08, 2011

Biomarkers Predict Success of Lupus Nephritis Drug Therapy

Identification of biomarkers that predict response to treatment of lupus nephritis with mycophenolate mofetil or pulse cyclophosphamide
Dall’Era, M, Stone D, Levesque V, Cisternas M, and Wofsy D. (2010).  Arthritis Care & Research (Hoboken): epub ahead of print.

What is the topic?
Kidney involvement (nephritis) can be one of the more serious complications of lupus. Even though outcomes have improved with more aggressive treatments in recent years, many patients still develop significant damage to the kidneys within 10 years of nephritis diagnosis.

Since lupus nephritis can be severe and the therapy can be toxic, it is important to be able to predict which patients would most benefit from long-term treatment. It would be particularly useful if specific factors could provide some advanced predictions about whether or not there would be successful responses to treatments for lupus nephritis.  

What did the researchers hope to learn?
The researchers hoped to identify factors that might be seen after 8 weeks of treatment for nephritis that might predict whether or not the treatment would be successful after 24 weeks. 

Who was studied?
The participants were mostly women, aged 20-41 who had lupus nephritis for 1-6 years. Patients were only included if nephritis was active by having a certain level of protein spilling into the urine (2 grams of protein in the urine during a 24-hour period) and the diagnosis of nephritis needed to be proven a kidney biopsy (a procedure in which a small piece of kidney tissue is removed for purposes of diagnosis). 

The following patients were excluded from the study: those who had recently received aggressive treatment for nephritis (cyclophosphamide or CYC) or mycofenolate mofetil (MMF) within the previous year, people who were on dialysis for more than two weeks prior to study entry, and those who had received steroids within the past two weeks.  

How was the study conducted?
The information came from 306 patients who participated in a clinical trial that compared CYC with MMF after study entry. The patients included were those who completed the first six months of the Aspreva Lupus Management Study (ALMS). ALMS was an international clinical trial for the treatment of lupus nephritis and included patients from many different countries and of different races. 

Patients received either CYC or MMF. All patients received prednisone starting at a maximum dose of 60 mg per day. The dose was gradually decreased every two weeks until a dose of 10 mg per day was reached. Patients could be taking ACE inhibitors (drugs used to treat protein spilling from the kidney and/or high blood pressure) but the doses had to remain stable throughout the study. 

A number of factors were tested to try to see if they would predict response to drug therapy for lupus nephritis at 24 weeks after initiation. These include the following: age, age at the time that lupus nephritis started, time since diagnosis of lupus nephritis, time since diagnosis of systemic lupus, whether the patient was a man or a woman, severity of lupus nephritis, how well the kidney was actually functioning, how much protein was spilling from the kidney, levels of antibodies such as anti-double-stranded DNA, complement protein levels, whether or not anti-cardiolipin antibodies were present, and the different background medications being used (including ACE inhibitors, hydroxychloroquine, and drugs to lower cholesterol levels in the blood).

What did the researchers find?
Improvement in lupus nephritis was evaluated after 24 weeks of treatment. About half of the patients receiving drug treatment for lupus nephritis met the criteria for a reasonable level of improvement after 24 weeks. 

Three things that were measured before the patients started the study predicted a successful response to drug therapy (regardless of whether the patients were taking CYC or MMF) after 24 weeks. These were kidney function upon entry to the study, the time since diagnosis of lupus nephritis, and the complement protein levels (C3 and/or C4). 58% of patients with good kidney function when they started improved after treatment as compared to 19% whose kidneys already showed some significant damage at the beginning of the study. 36% of patients who were diagnosed with lupus nephritis 1-5 years before entry into the study responded to drug therapy while 61% who were diagnosed less than a year before the study responded. Of those patients who started the study with low levels of C3/C4 complement proteins, 59% responded to therapy but only 47% of those with normal levels of C3/C4 responded. 

The investigators also looked at how the patients were doing at 8 weeks and if this could predict how they were doing at 24 weeks. If the protein spilling from the kidney decreased by 25% or if complement proteins C3 and C4 went back to normal by 8 weeks, then it was more likely that the patient would be considered significantly improved at 24 weeks. A decrease in levels of anti-double-stranded DNA after 8 weeks of treatment did not predict treatment response after 24 weeks. 

What were the limitations of the study?
The study looked at responses to treatment for lupus nephritis after 24 weeks. 24 weeks may not be sufficient time to see maximal responses to therapy for lupus nephritis for all of the patients. On the other hand, if a person does respond by 24 weeks, then this is optimal for the long-term health of the kidney. Still, it is important to keep in mind that if a longer treatment time is considered, additional factors could become predictive of responses to treatment. Also, this study was a “post-hoc analysis,” meaning that the statistical analyses performed on the study results were not pre-determined at the start of the study. This makes it an exploratory analysis. The rules of statistics would require this information to be confirmed by another study before a final conclusion can be made. Nevertheless, this information could be very important, on a practical level, for lupus patients and their doctors by providing some guidance at earlier stages of treatment about whether to consider increasing treatments or whether or not steroids should be tapered yet.   

What do the results mean for you?
At the start of treatment for lupus nephritis, the complement protein levels and kidney function, as well as the time since diagnosis of lupus nephritis, predicted the chances that standard treatments would work. These factors can thus help physicians and patients decide how aggressive to be in the choice of therapies. Once 8 weeks of treatment have passed, this study suggests that improvement in the complement and levels of protein in the urine might serve as a valuable guide to how well things are going with the current treatment and help in the decisions about whether to increase treatments, hold a steady course, or start to taper steroids. Because this is an exploratory study, no statistical conclusions can be drawn. However, with the lack of guidance about these issues that we currently have, and the fact that these findings make clinical sense, this study provides a critically important milestone that physicians are likely to take very seriously.

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