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  1. 1. Sangeeta Sule, MD Hi everyone, I am going to talk today about pediatric lupus and clinical abnormalities in pediatric patients with lupus. I have nothing to disclose. The objectives today are to define the differences between pediatric and adult patients with lupus and then, because I am now in the Division of Pediatric Nephrology, I am focusing on pediatric patients with SLE and renal disease; so, that will be the final objective. Just like in adults, pediatric patients with lupus can have very variable pictures. So you can see there a typical malar rash on the right hand side, a discoid rash to the bottom right hand side, kidney disease, arthritis, autoantibodies, just like in adults can present multiple different ways. There are many retrospective studies about comparing differences in pediatric and adult patients but very few, and I will come to it in just a second concurrent studies, comparing pediatric and adult patients. This chart is a compilation of multiple different studies showing what people estimate to be the difference between pediatric, defined as less than 18 years of age at the onset of disease and adult patients. So you can see here that the first striking thing is that the female to male ratio is thought to be different in pediatric and adult patients, whereas in adults there is a strong female predominance of 10 to 20:1; in pediatric patients, particularly prior to puberty it is not as striking, but we actually have two or three boys in our clinic before puberty who we follow. The percent black race is pretty much equal between the two. Percent kidney disease though is in red because that is the area that I will focus on later, you can see there that the estimates are very wide, 50-80% of pediatric patients have some degree of renal involvement, varying anywhere between focal proliferative glomerulonephritis to diffuse proliferative glomerular nephritis whereas an adult’s that estimate is very variable to 20-50%. Percent CNS
  2. 2. disease thought to be higher in pediatrics and the percent with initial disease diagnosis of hypocomplementemia is thought to be higher in pediatric patients with a low C3. So one of the, and you probably have seen this in just recently published in Arthritis and Rheumatism just this past February, one of the largest studies to try to look concurrently at pediatric and adult patients with lupus was done at Toronto. What they did is they took patients followed between 1990 and 1998, followed until February of 1999 and they took an inception cohort of 67 children, childhood onset, defined as age less than 18 and compared it to an inception cohort of 131 adult onset lupus patients. This chart focuses on the renal involvement. That is one of the most striking differences between peds and adult patients. You can see here in the childhood onset lupus, almost 78% of the patients had some degree of renal involvement, varying anywhere between focal proliferative to diffuse proliferative glomerulonephritis, compared to 52% of the adult patients with a highly significant P-value of .0005. Most pediatric patients had at least one renal biopsy, 64%, compared to 18% in adult patients and then the class of renal involvement didn’t seem to vary that much. The class-4 diffuse proliferative 40% of children had that compared to 32% of adults. There wasn’t a statistically significant difference between those two. So as you might expect, if children have more severe disease then they require more aggressive immunosuppressive agents. You can see here that almost 97% of children were tried on oral corticosteroids initially at disease onset and then throughout the follow-up period, compared to adults of 70% which was a highly significant difference. In addition, immunosuppressive medications were more often continues in children with 66% of children continuing on some immunosuppressive agent compared to 37% of adults, the most common of which is azathioprine. Also interestingly the study
  3. 3. looked at disease activity as measured by the SLEDAI with a maximum score of 105 measured in different organ systems at the maximum score and the score at diagnosis and you can see there that the childhood maximum score is 69 out of max of 105 compared to 45 out of the adults. Also the SLEDAI score at diagnosis was 16.8 mean compared to the adults of 9.3 with a highly significant T-value. In addition the last row, the mean SLEDAI score was much higher in children compared to adults. So the overall sense from that study (interrupted by conference attendee).... so the Toronto patients are mostly Caucasian, there were 80% Caucasian, and predominantly female so it is different than like Michelle’s cohort or what we would see here. So as you can see from all this data pediatric patients may have more active disease at presentation and then throughout their course, but what does that actually translate into? Does disease damage differ? As you can imagine there is not a lot of data about this, as there just aren’t a lot of pediatric rheumatologist out there to study this. This is a compilation of different studies looking at 31 pediatric patients and the damage index, which was 2.6 with a potential maximum of 46 after 4.7 years. This is compared to historical adult controls where the cumulative damage index was .75 after five years. In a larger multicenter study of 387 pediatric patients from Europe, U.S., Mexico and Japan who were followed for eight months showed significant end stage organ damage, most commonly in the kidney, almost 22% have some sort of kidney damage in pediatric patients. (Question from attendee – inaudible)..... It could, when they compared the statistics between adults and kids, male female predominance, non-Caucasian, there wasn’t a statistically significant difference but that is a good point just in general to consider. (Question from attendee – inaudible).... Very much so, or the other thing is the adult patients, or all pediatric
  4. 4. patients would get referred to a pediatric rheumatology center. (Question from attendee – inaudible).... Right, that is a good point. That’s what they said. It was based on their clinical practice. There were different doctors seeing the two sets of people. Urinalysis, proteinuria and hematuria. I can say it just based on my own experience working in the pediatric clinic, almost every child with a minimal degree of proteinuria would get biopsy whereas that may or may not be the case in adults, because that is clearly abnormal in a child. (Question from attendee - inaudible)... Whereas in kids any degree, unless it is orthostatic proteinuria or clears with the first morning urine, any child would get a biopsy because that is not normal in a child. Going back to that Toronto study, they also looked at disease damage and the difference between disease damage in childhood onset lupus and adult onset lupus. This is a large table so I just boxed in red the only significant ones, ocular damage and the musculoskeletal score were different with higher scores in pediatrics. That is interesting because the disease activity scores in the kidneys were higher in kids versus adults but that doesn’t translate in this study to disease damage, the third one down there, renal damage, that wasn’t statistically significant between kids and adults. So we know presumed disease activity is different between kids and adults, disease damage may be different between kids and adults but what about survival in pediatric lupus patients. There is actually not a lot of data about this. The one study at the time was actually from Michelle, looking at the Hopkins lupus cohort, following our patients between 1987 and 2004, the survival time was determined from the time of lupus diagnosis to the last contact or date of death. So she had 1,378 patients in the study, the mean age of lupus diagnosis was 32.3 years plus or minus 12.8 years but you can see the range is a very broad, five to 75 years. So at the time of analysis there
  5. 5. were 118 deaths, 8.6% over the median length of 6.1 years of follow-up in the cohort. So this is survival from the years since diagnosis, so from 0-40. The red arrow is pointing to the younger group, those less than 16 at the time of diagnosis. You can see here, according to this analysis, this is about 97 patients in the less than 16 groups, but they did better than all the other age categories. In the table format displayed here, the age of diagnosis less than 16, 10 out of 97 patients died but that wasn’t the estimated probability of 20 years survival that wasn’t significantly poor. So the other thing that Michelle’s study looked at was the association based on disease manifestations and survival and what baseline do these characteristics were associated with poor survival. She looked at neuropsychiatric disease, renal disease, pulmonary disease, hematologic disease and hemolytic anemia and adjusted for age, ethnicity and sex. The only thing that was significant in the adjusted analysis was this black coloring, the 2.5 for the hemolytic anemia. It is interesting because renal disease did not end up being statistically significantly associated with poor survival. Okay, so that is some of the background of pediatric versus adult lupus. The challenges that we have in pediatric lupus (question from attendee – inaudible)….She said the most common cause of death was infection in that group, in the hemolytic anemia group, in the greater than 50-year-old group. Overall the most common cause of death is infection. I will come to that in a second when I present some other data about causes of death in children with renal disease and what that is proposed to be. So some of the challenges in pediatric lupus are that it is rare. It effects between five and 10,000 children in the U.S. and it is more prevalent in the teenage years, so like Dr. Wigley eluded to, some of the younger kids may percolate along and may not tend to
  6. 6. present to a physician’s attention until they are older and that becomes a challenge of trying to study this disease. Harkening back to the fact that it is thought that pediatric patients with lupus have an increased prevalence of renal disease, so we are going to focus on that subset because now being in the Division of Pediatric Nephrology we have access to different nephrology data sets and I will present that data here. So, we are going to switch and talk about kidney specific guidelines and what we have been looking at in our research studies here. The National Kidney Foundation and Kidney Disease Outcome Quality Initiative Guidelines have been set for key areas in management of patients with end stage renal disease. Achievement of these cutoffs has been shown to improve morbidity and decrease mortality in both children and adults with end stage renal disease. In order to look at whether children and adults are achieving these targets, the Centers for Medicare and Medicaid Services have initiated this project called The End Stage Renal Disease Clinical Performance Measures or ESRD CPM project to determine if clinical targets are being achieved. The reason that this has any significance at all is because they are thinking about moving towards payment reimbursement based on whether these targets are achieved and how dialysis centers are doing with meeting these targets. So in 1994 they began collecting data on random samples of in center adult hemodialysis patients. Adolescent patients 12 to 18 years old were included in 2000 and then in 2002 all pediatric patients receiving hemodialysis around the country were included in this analysis. So the way they collect this data is that all pediatric patients identified as alive and receiving hemodialysis during the yearly data collection period, the preceding October, November and December are included and the minimum data needed for inclusion are at least one monthly hemoglobin and albumin level, a pre-
  7. 7. dialysis and post-dialysis BUN level. What we did initially was do a cross-sectional analysis comparing lupus patients in this data set, pediatric lupus patients, to see whether they achieve the recommended clinical targets compared to other pediatric patients with end stage renal disease. So what we did was we looked in the data that was available for pediatric patients from 2000-2004 and compared lupus patients to other pediatric patients. Our hypothesis was that pediatric patients with lupus would be less likely to achieve these recommended clinical targets compared to other children maintained on hemodialysis. We used T-tests and Chi-squared tests and logistical aggression analysis to look at this. When we looked at the logistical aggression analysis other cofounders that we controlled for include age, gender, race, time of receiving dialysis and other clinical targets. So what are their guidelines and cutoffs? These are pediatric specific ones now, including hemoglobin greater than or equal to 11, vascular access type, whether they have an arterial venous fistula or graft and whether they maintain a serum albumin greater than 3.5. There are 98 in this data set, there are 98 pediatric lupus patients and 1,822 other children with end stage renal disease receiving hemodialysis. These other diagnoses are primarily urologic disease, the most common cause of posterior urethral valve syndrome. There are 682 patients with glomerulonephritis alone, not urologic disease. We also did the analysis comparing lupus patients to just glomerulonephritis and these same statistical differences applied. You can see that the lupus patients are slightly older than the other children, 16 years with mean age compared to 14 in the other children. There is a higher percent female of 80%, more African-American race as you would expect, the time on dialyses less than six months, 61% of the lupus patients were on dialysis for a shorter period of time compared to 39% of the other diagnoses. There
  8. 8. was no real difference in the mean BMI. Going back to those clinical targets of albumin, whether they achieve their fistula placement and whether their hemoglobin is maintained above 11, you can see here that the lupus patients failed to achieve the serum albumin level in cross-section analysis and failed to get permanent access placement for the hemodialysis. There were no differences between the mean hemoglobin achievement between lupus patients and other patients. Now in this data set it doesn’t give us what medications they are on or disease activity or other confounding things that may affect a serum albumin level, but this is still a pretty striking difference. So what factors in general were associated with not meeting the serum albumin targets? You can see there that the diagnosis of lupus in the unadjusted odds ratio, lupus patients were three times less likely to make the albumin cutoff level and an adjustment for age, gender, time on dialysis and the other targets have still held true because patients were almost two times less likely to achieve serum albumin levels. This is even compared to patients with glomerulonephritis including MPGN, Wegner’s, post-strep. The same holds true for the pediatric lupus patients compared to other patients about whether they were able to get a permanent access for their dialysis so that lupus patients were almost three times less likely to get permanent vascular access for their hemodialysis compared to other children. You may say why does that matter? It would be kind of intuitive that lupus patients would have a lower albumin and would be more likely to have vascular catheters. The reason that these are actually government indicated guidelines is that those factors have been associated with increased mortality in patients receiving hemodialysis with end stage renal disease, so that is important to monitor. The next question becomes in a cross-sectional analysis lupus patients don’t achieve these targets? What about if you
  9. 9. follow them over time? Are they able to achieve these targets if they aren’t followed with their hemodialysis? So what we did with this analysis was look between 2000 and 2004, the data set that we have, whether over time the are able to achieve the albumin and vascular access target and adjust for the other potential confounders. So the longitudinal logistic aggression analysis was used as our statistical analysis. Again, just reminding you of the cutoffs, with a hemoglobin greater than 11, permanent vascular access and serum albumin maintained above that level. So, first off, the first question is how many lupus patients were followed longitudinally? We know there were 98 total in the data set, 29 followed for one year, 19 for two years, eight for three years and then one for one to five years. Where did they go? Some of them graduated, you remember the mean age was 16, so they were older to start with. This includes only patients less than 18. Some of the graduated to the adult world. Two of them got a renal transplant and one died. This graft table is asking the question whether these lupus patients were able to achieve albumin targets over time, comparing lupus patients to the other patients, excluding the fourth and fifth year of follow-up because there are only one lupus patients in each of those groups. So it is study year, one, two and three. You can see there the adjusted odds ratio for the lupus patients is 1.15 and 0.46, they are still even over time not achieving their serum albumin targets. Neither are the other patients, 1.05 an 1.06 is the reference for the other patients, so really none of the groups are achieving their serum albumin targets over time. (Question from attendee – inaudible)….Yes, that is because at the study year three there were only eight lupus patients. We actually thought about excluding study year three but we didn’t. (Question from attendee – inaudible)…. There are 19 patients who were followed. When you think about it the largest data set we have
  10. 10. of pediatric lupus patients, but when you stop and think about it, it is actually still a pretty small number. (Question from attendee – inaudible)…. This data set is only pediatrics because it is pediatric nephrology. (Question from attendee – inaudible)….No, what I mean is my mentors have access to the pediatric data set. (Question from attendee – inaudible)…. We did link it to an adult type data set to look at survival and I will show you that in just a second. (Question from attendee – inaudible)…. Remember these are all patients with end stage renal disease on hemodialysis so their year of diagnosis may have been at age 10, 12 whatever, but by the time they developed end stage renal disease some time must have passed. The next question, the other marker that they didn’t meet initially was whether they have permanent vascular access placed and that is important because the more temporary vascular access is associated with increased risk of infections. So over time, just like Anthony pointed out, this is even a larger competent sample, that the lupus patients did not get permanent vascular access. So these are the patients who are staying on hemodialysis, or on hemodialysis for three years has still been using temporary access. Compare that to the other non-lupus patients who are receiving hemodialysis they all did achieve permanent vascular access placement. So the conclusion from that one was that pediatric patients with lupus over time were unable to achieve serum albumin and vascular access targets compared to other pediatric patients with end stage renal disease who did get permanent vascular access place. What does that mean? The big question is what does that translate into? The failure to achieve these clinical targets negatively effects lupus patient mortality. It has been shown in other population to effect mortality if you did not achieve these targets. (Question from attendee – inaudible)….That is true too. It is not clear why. If it doesn’t make any sense
  11. 11. if someone is getting hemodialysis for three years why they wouldn’t get a fistula placed and the in just talking amongst our group, things that could have come up, or whether they thought it would be more temporary in lupus patients, the feeling was that that end stage renal disease would resolve. If lupus patients were having for instance diffuse proliferative glomerular nephritis and getting Cytoxan or other immunosuppressant treatments was the feeling that this would eventually help and they would reverse out of renal failure. That data is not there. So in order to tell whether this has any impact on mortality you have to link this CPM data set to another data set. So this other data set is from the ERDS Project and it is operated by NIDDK and the Centers for Medicare and Medicaid Services. This data set collects data from all medicare reimbursed patients who received renal replacement therapy, hemodialysis and peritoneal dialysis since 1977. It is estimated to include about 95% of adults and about 70% of children who received renal replacement therapy in the U.S. So in order to answer the question about mortality, there are multiple different ways to do it. What we decided to look at is take those same 98 patients from the CPM data set and link those patients to the ERDS data set where we have data on mortality and see whether their inability to achieve clinical targets effected their mortality. So that is what I just described. We did Kaplan Meyer survival analysis and cox proportion hazard analysis and they were censored at transplantation which for the lupus patients wasn’t many. So that is just graphically the way we were looking at this question. So in these pediatric patients with end stage renal disease, in the one to five years of follow-up, remember from the CPM data set, linked now to this larger data set, there were 12 deaths in the lupus patients, so 12% of the lupus population died. There were 85 deaths in the other patients, 1,822 patients, 4.7% with other causes of end
  12. 12. stage renal disease. And Stewart, your question about how they died, this population was all infectious complications, for the lupus patients. In the lupus patients one had a PE but the majority was infectious. So this is the survival analysis with the other patients on the top line in the blue and the lupus patients in the red line. The analysis time is the time of the CPM data set with one being they are alive and then each bump being a person who has died. You can see first off that the lupus patients tend to die off, there is a steep slope, they die off early compared to the other patients, there are more patients there, but it is a more gradual decline in their slope. (Question from attendee – inaudible)….So in looking at the Cox Proportional Hazard Model for mortality and adjusting for age, race and gender, and also our main question about whether lupus patients died more often or whether the failure to achieve targets effects deaths, you can see that the lupus patients, unadjusted and adjusted have a threefold higher risk of death compared to other pediatric patients with end stage renal disease and that failure to meet hemoglobin and albumin was also associated with increased risk of death. So the conclusion is that pediatric patients with lupus were threefold more likely to die compared to other children with end stage renal disease receiving hemodialysis and that increased mortality was significant even when controlling the other clinical characteristics and whether they achieved other clinical guidelines as recommended. (Question from attendee – inaudible)….We don’t know any of the medicine so I don’t know what the lupus patients were on and I don’t know what the other patients were on. That is a good question. They died of infection but that can be from all sorts of things. No it just says infection. (Question from attendee – inaudible)…. Not in the data that we have. I am sure there is a way to access it, about more specifically what they died from. (Question from attendee – inaudible)….It is hard
  13. 13. to tell because those patients like Anthony pointed out, the mean age of these lupus patients was over puberty so the mean age was 16 and it is thought that in kids it is before puberty where the male, female predominance is not as striking so it is hard to tell. In the two male patients that we have they both have significant renal disease. Neither one are on hemodialysis but they have significant renal disease. (Question from attendee – inaudible)…. There is so much other data that is missing from these data sets that pertains to lupus but that is not what the data set was designed for. It was designed to determine whether the hemodialysis centers were meeting these documented cutoffs that have been shown to improve morbidity and mortality in other population so they are not designed specifically lupus patients. A lot of things are missing like medication, other organ involvements or for all we know all the lupus patients also had CNS disease or other organ systems involved. That is not listed there. So you are right, there are a lot of confounding factors there. The main question, because I am in a group of nephrologist, their main question of interest was whether lupus patients meet these targets because those targets have an importance in the nephrology world. (Question from attendee – inaudible) It is a place to start basically. (Question from attendee – inaudible)… These are all on hemodialysis. We don’t have any kinds on hemodialysis in our group. But, the reason that it was focused on in the nephrology world is that in other populations, not lupus but in other populations, failure to achieve those targets was associated with significant morality which is why it is now almost linked to reimbursement, whether you achieve these targets or not in your hemodialysis population. (Question from attendee – inaudible)…. So that is a good question. They have looked at that in other populations and when you do give them Epogen and get their hemoglobin above 11 their mortality
  14. 14. decreases. I think that is why those targets were developed, those specific ones where looked at, but you are right there are a lot of confounding factors in the lupus patients that this may or may not be relative to. (Question from attendee – inaudible)….Apparently not. There is not a lot of written reports about this. A lot of it is just anecdotal in talking to the nephrologist in our group and they said no, their lupus continues, a lot of them still require Cytoxan, CellCept or _______(Question from attendee – inaudible)…. So we are setting up this cohort, this is what working with Anthony and Michelle, we are setting up this cohort based on Michelle’s model, working with Anthony and Philipe and that is just kind of a quick overview of what we are doing; but there are about 20 patients right now collected over two years, so about 10 per year. Out of those there are two boys who when they were first diagnosed at age 12, the majority of the patients over 80% are African-American and the mean age is like 14.8 years but the range can go anywhere, the youngest at age of diagnosis was 7 up to 16. After age 19 we don’t follow them usually in clinic, they transition to an adult rheumatologist. (Question from attendee – inaudible)…. Hopefully, that is the goal. Eventually what we would like to do, is because most of these studies compare pediatric population to historical adult controls the goal would be to in the same area, compare simultaneously collected data in pediatrics versus adults to see if there is a difference between activity damage and just presentation, whether renal disease really is more common in kids. (Question from attendee – inaudible)….out of the 20 that we have, about 18 have received Cytoxan. Out of the 20, all 20 have some degree of renal disease, focal proliferative to diffuse proliferative and in those 18 out of the 20 have diffuse proliferative. (Question from attendee – inaudible)…. no just lupus. (Question from attendee – inaudible)…. Right and you can imagine as a
  15. 15. parent, like if you approach someone with a list of immunosuppressant agents and tell them the side effects from all of them, if you had to choose as a parent you would choose something less aggressive like Imuran as opposed to Cytoxan for the risk of infertility or malignancy which is higher. (Question from attendee – inaudible)….Well, luckily none of them were on dialysis. Just talking to the group they had a couple, a handful who received dialysis and they got hemodialysis, that was before peritoneal dialysis became more commonplace. They received hemodialysis and they got a permanent catheter. Here they are very aggressive about early on putting in fistulas for grafts. (Question from attendee – inaudible)…. Do we, yes. They never had the shunt offered to them so they were getting temporary dialysis so there was something prohibitive about the fact that they were never offered that. Race was included. We did adjust for race, gender, etc. When you look at it individually, unadjusted analysis, there was no difference between race in the unadjusted analysis, about whether they did or didn’t achieve targets, the albumin, hemoglobin or vascular access. We didn’t do an interaction term to see whether lupus patients with black race are more at risk for that. (Question from attendee – inaudible)….not in the CPM data set, no. In the ESRDS data set, a larger data set they do have that data but not in the CPM data set. Thank you,