4/28/21 – Hermine Brunner, MD, MSc, MBA - Childhood-Onset Lupus

Name: 4/28/21 – Hermine Brunner, MD, MSc, MBA - Childhood-Onset Lupus
Uploaded: 2021-04-29T16:56:28.523Z
Duration: 1 h 1 min 16 s
Description: For CME Credit, please read the CME announcement for this lecture . For Community Practitioners , please read the following CME announcement .

April 29, 2021

For CME Credit, please read the CME announcement for this lecture.

For Community Practitioners, please read the following CME announcement.

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ID: 6542
To Cite: DCA Citation Guide

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00:00Get started, thanks.
00:08So the. Mary Jane Keller lecture
00:16is in honor of Mary Jane Keller, who.
00:19Live born in 1960 and passed away in 1970.
00:25Doctor McCarthy I've got.
00:26I'm gonna start with a few announcements.
00:30OK, go ahead and click.
00:31I don't think we will start in just a second.
00:35I'm gonna let people come in and
00:37then and then I'll call on you.
00:40OK, great. Alright.
00:45So I'm going live.
00:48Will follow Doctor Bochs lead.
01:16While everybody is joining, will wait
01:18just a minute and we'll get started.
01:20So give it another minute or two
01:22to allow people to get into our Web
01:24and R and then we'll get started.
02:56Alright, well good morning everybody.
02:58Welcome to pediatric grand rounds.
03:00So happy to have you today.
03:03I just have a few announcements
03:05before we get started.
03:07Our next week's grand rounds.
03:11Is Renee Barrett, who is the
03:14assistant who's our assistant
03:15professor of Pediatrics in the section
03:19of Neonatal Perinatal Medicine.
03:21She'll be doing an Eminem case
03:24presentation and then the next week
03:27is our Yelp Pediatric Research Forum.
03:30And will actually be having.
03:37Sally permar giving Grand Rounds is a grabber
03:43powers lecturer on it's congenital CMV.
03:55So the yellow Pediatric Research Forum starts
03:58next week and this is going to be via zoom.
04:02You all should have received a schedule.
04:05There are going to be multiple
04:07sessions each day on different topics.
04:09We have our opening keynote speaker
04:12who is sharing Shrinivas car,
04:14a chair at UCLA.
04:15Mattel Children's who is also this years.
04:19Award winner from the APS.
04:23And she'll be opening our research
04:25forum and then closing.
04:27As I mentioned to Sallie Permar.
04:34There is no commercial support for this
04:36grand rounds and there are no conflicts
04:38of interest that need to be resolved.
04:43And you'll get CME or CNE credit using the
04:45zoom credentials that you signed in with.
04:48And please write your questions in the
04:50Q&A section of the zoom at the end.
04:55And at this point I would like to turn
04:59the program over to Paul McCarthy,
05:01who will introduce the Mary Jane
05:04Keller Memorial Lectureship as
05:06well as today's special speaker.
05:08Thank you Paul. Thanks Cliff.
05:12This is the Mary Jane Keller Memorial
05:14Lectureship, which has been in
05:16existence for more than 40 years.
05:18It's was established in
05:20honor of Mary Jane Keller,
05:22who was born in 1960 and passed away in 1970.
05:26After a year of battling dramatic myositis.
05:30She was a daughter of Ginny and Diane
05:32Keller and the sister of an Edward and Amy,
05:35some of whom are joining us today in Zoom.
05:38This lecture was established as a
05:41lasting legacy to Mary Jane who was
05:44taken care of by our former chair.
05:47See Gavin Court Cook,
05:48who did many of the pioneering studies on
05:52the use of steroids and dramatic myositis.
05:56And Mary Jane benefited from that.
05:59But this lectureship is is established
06:02a sustained excellence in teaching
06:04patient care and research in
06:07rheumatology immunology and related
06:10disciplines here at Yale.
06:12In in the tradition of the superb
06:16speakers that we've had in the past,
06:19today's speaker is certainly in that line.
06:22Determann bruner.
06:25Is head of pediatric rheumatology
06:27at Cincinnati Children's Hospital.
06:28She has a very interesting
06:31background and that she has an MBA
06:34in market research and worked at
06:37Siemens before going to Med school.
06:39Received RMD from Ludwig
06:42Maximilian University.
06:43An internship at the same University
06:45residency at University of Chicago.
06:48Wilder Children's and then obtain
06:50a master in clinical Epidemiology
06:52and at University of Toronto and
06:54did a fellowship both at Toronto
06:56and Cincinnati Children's Hospital.
06:58Currently, as I said,
07:00she's professor of Pediatrics at
07:02at Cincinnati Children's Hospital.
07:04Head of the Division of Pediatric
07:06Rheumatology, and has endowed chair there.
07:10She's also director of the Cincinnati
07:14Children's Lupus Center.
07:16She has had many important.
07:21Obligations nationally.
07:22She is on the Scientific Advisory
07:26Council of a Lupus Foundation.
07:28She is a head of the Pediatric
07:32Rheumatology Collaborative study group
07:33and many of that effort has focused on lupus.
07:37He was chair of the pediatric
07:40portion of the ACR annual Meeting.
07:43She also chaired the R34 study section
07:46for clinical trials at the National
07:49Institute of Allergy and Infectious Disease.
07:52She is the associate editor of
07:55Arthritis Care and Research.
07:57At Cincinnati,
07:58she's very active in patient care.
08:01She heads the Lupus center.
08:03As I said, she's served as a mentor
08:06to more than 50 undergraduates,
08:09fellows and postdocs.
08:12Her publications number 180 and
08:15she is first author on 50% of
08:18those publications quite a record.
08:20She's had continuous support
08:22and grants and contracts.
08:25Her work primarily is focused on.
08:30Juvenile arthritis and lupus, and in lupus?
08:33She's looked at genetic factors.
08:38Relating to propensity to lupus.
08:40Looked at biomarkers for lupus
08:43nephritis and also how to use those
08:46biomarkers for loss of renal function.
08:50She's written on the induction
08:52therapy for lupus glaring on the
08:55frites has assessed neurocognitive
08:57status of patients with lupus.
09:00Looking at brain imaging, it's cerebral.
09:03Microvasculature has established
09:05severity index for cutaneous lupus.
09:08Anne has also established criteria
09:10for response to lupus therapy,
09:13measuring remission and academic outcome
09:15in eseli I think very important to all
09:19pediatric and adult rheumatologist.
09:20She actually led the effort in establishing
09:23the safety and efficacy of Bella minimum Bab,
09:26which is of benlysta,
09:28which is the first drug that was
09:30a staff that was researched with
09:33a focus on therapy for lupus.
09:35She's also looked at pharmacokinetics
09:37of Cellcept and lupus so she has
09:40a remarkable record in pediatric
09:42rheumatology and we're delighted
09:44to have her here today and also.
09:47Know that she is.
09:51We look forward to her talks in
09:53the Mary Jane Keller Lecture.
09:56So Doctor Bruner thank you
09:58very kind invite and now come I try
10:01to share my slides. In a second.
10:22Almost there.
10:24So on getting my slides up.
10:27I need to confess that I
10:31have bad allergies today.
10:33And I will try to do my best to talk
10:36clearly and not cough in the microphone.
10:40Today the topic of my talk is
10:43comprehensive quality triffin care of
10:45adolescents and children with lupus.
10:49Here are my disclosures.
10:55As you will get to see me for
10:58these talks, we have objectives.
11:00I will inform you about
11:01established standards for the
11:03treatment of children with lupus,
11:04educate you on the need of
11:07multidisciplinary care.
11:08Update you on the surveillance
11:10and treatment of brain disease
11:12in children with lupus and
11:13also about the diagnosis and
11:15treatment of lupus nephritis.
11:19Before I go into these objectives,
11:21let me introduce childhood onset,
11:23lupus childhood onset bloopers is defined as
11:27onset of lupus prior to the age of 18 years.
11:31Indeed, about 15 to 20% of all
11:33persons who are diagnosed with lupus
11:35have been diagnosed during childhood
11:37and different from adult cohorts.
11:39There are more males in
11:41among pediatric patients.
11:42Indeed, about 20% of them are male.
11:46The most frequent age of diagnosis is around
11:49the time of puberty between 12 and 14 years,
11:52and it's rare that you will
11:54diagnose a patient with lupus prior
11:57to the age of five years.
11:59When diagnosing children with lupus,
12:01we often use the classification
12:03criteria that have been developed by
12:06the American College of Rheumatology,
12:08primarily for the conduct of research,
12:10but we also use them in a clinical settings.
12:14This classification criteria have
12:16recently been updated and we showed in
12:19our publication that these classification
12:22criteria work similarly well in children
12:24as they do in adults with lupus.
12:30How does the presentation of children
12:32in adults with lupus differ?
12:34Well, the principal features of adults
12:36and children with lupus are the same.
12:39They are identical.
12:40However, children with lupus have a more
12:43acute onset of disease and they have
12:45much more often multiorgan involvement.
12:48This results in children with
12:50Lupus having 5020 up to 20% more
12:54often fever and lymphadenopathy
12:55during the course of the disease.
12:58They developped 30% more often renal
13:01involvement as part of their disease.
13:04They have more common haematological
13:07abnormalities and they also have 10 to 15%
13:10more commonly neuro psychiatric disease.
13:16Well, a couple of years back we wondered
13:19how does one provide comprehensive
13:21care for a complex disease like lupus.
13:24While we would like to provide high
13:26quality of care and that quality of
13:29care or medical care has been defined
13:32by the Institute of Medicine as the
13:34degree to which health services for
13:37individuals and population increase,
13:38the likelihood of the desired
13:40health outcomes.
13:41Probably high quality of life and
13:43good survival and are consistent
13:45with current professional knowledge.
13:47In this context,
13:48very often quality indicators are used
13:51to operationalize quality of care so
13:54they are definitions that are used
13:56to define a minimum standard of care.
13:59Quality indicators are based
14:01on scientific evidence,
14:02they based on medical experience,
14:04and it is assumed that if a tearing
14:07through this quality measures
14:09and fulfilling this quality,
14:11indicators that broke noses,
14:13and the outcome of the patient
14:16will be improved.
14:18Scientific medical evidence can be created
14:21and there are various systems to do so.
14:24The one I like best is the Oxford Centre
14:27of Evidence based Medicine criteria.
14:30Here's the website for you to look
14:32it up and they create medical
14:35evidence in categories.
14:37A 2D based on the type of study
14:40that provides the evidence.
14:42Expert opinion is considered very low.
14:45Randomized clinical trials constitutes
14:47the highest level of evidence.
14:52Several years back,
14:53a team which I had the honor to
14:56lead went ahead and tried to define
15:00quality indicators for patients
15:02or which for children with lupus.
15:04We underwent an international consensus
15:07formation process in the countries that
15:10participated are shown on the slide.
15:12First we started with a large and in
15:15depth literature review to establish
15:17the current scientific evidence
15:19and then be engaged over 300.
15:22Expert physicians around the
15:24world who regularly treat children
15:27and adolescents with lupus.
15:29Consensus was defined as agreement
15:31among these experts of 80% and higher.
15:36In order to be considered in
15:38this project also,
15:39the established quality
15:40indicators for adults with lupus.
15:42So if you ever want to look that up,
15:46but our quality indicators for
15:48children which with anti defined are
15:51stricter and there also consider
15:53transition of care to adult providers.
15:57One of the quality indicators was
15:59that one should regular measure
16:01disease activity with lupus using
16:03a tool like the systemic lupus
16:06Disease Activity index that basically
16:09quantified the amount of active
16:11inflammation which you can treat
16:13with anti inflammatory medication.
16:15One should also assess the degree of
16:19damage with lupus and that's the error.
16:22Irreversible scarring or degradation
16:24of function due to prior inflammation.
16:27Lupus,
16:27or due to the treatment we rendered
16:31as physicians?
16:32One should not forget to assess
16:34patient pain and well being,
16:36and that can be done quite easily
16:38using visual analog scales.
16:43One of the quality indicators for
16:46lupus is for children that all
16:49children should be treated with anti
16:52malarias and have an annual eye exam.
16:55And why is that while there is
16:58actually excellent scientific level
17:00evidence that use of hydroxychloroquine
17:02is associated with reduction of
17:05lupus associated disease activity,
17:07it's associated with reduced mortality.
17:09It helps preserving bone health
17:12prevents from bocice. And organ damage.
17:15Those slower create evidence for other.
17:19Important outcomes and the one I would
17:22like to point your attention to is the
17:25protection from cancer and this is
17:28important because children with lupus
17:29have a 3 1/2 time higher cancer risk
17:32than their same-sex peers or same age peers.
17:39Stated all children should be treated
17:41with antimalarials and they should
17:43have an eye exam. Why is that?
17:45Because one of the most feared side
17:48effects of hydroxychloroquine,
17:50besides the arrhythmias you will
17:51get if you dose it five times
17:54higher in the context of covid
17:56is I toxicity and I toxicity.
17:59Prevalence increases with the
18:00duration of disease is out with
18:02the duration of medication intake.
18:04Now when you have a child
18:07with lupus diagnosis.
18:0814 We would hope that
18:10the survival is at least,
18:12you know, another 4050 years,
18:14but when you look over here
18:16on this figure to the right,
18:18after intake of hydroxychloroquine,
18:20let's say just for 20 years at
18:23the current dose Ng regimen.
18:24You will have about a 20% risk of heroes,
18:28versible eye toxicity with the
18:30intake of hydroxychloroquine.
18:32In the past we dosed
18:34Hydroxychloroquine evening,
18:35more liberal with doses higher
18:37than 5 milligrams per kilogram,
18:39and if we had continued that
18:41like we did 10 or 15 years ago,
18:45the risk of a child with lupus
18:47after 20 years of disease duration
18:50provided they were treated with
18:52hydroxychloroquine will almost be 50%.
18:55I toxicity with loop from hydroxychloroquine.
18:57It's not reversible.
18:59How to be screened for that?
19:01We do assedio cities and we
19:04do automated visual testing,
19:06but will sometimes see in older.
19:10Xbox is fundus examination,
19:12but that's not very accurate.
19:14When you do STOCT,
19:16one of the early markers is power,
19:19foveal thinning,
19:20and that leads to the flying saucer sign.
19:24Maybe an exam question for you guys.
19:29Well before we have steroids
19:31for the treatment of lupus,
19:33the average survival of a child
19:36with lupus was two years.
19:39Nowadays children's survival
19:41with lupus in the United States
19:43is over 95% at 5 and 10 years,
19:47so that means that cortico
19:49steroid use among the use of
19:52other treatment has drastically
19:54improved the prognosis of lupus.
19:56It's custom to use a dose of
19:59about 2 milligrams per kilogram,
20:01with the maximum dose shown on the
20:03slide and in rheumatology with sometimes.
20:06Divide the dose of steroids in one to
20:09four daily doses and the rationale
20:11for that is that if you split the
20:14dose from once to twice daily,
20:16you increase the exposure to
20:19hydroxychloroquine and not to
20:21hydroxychloroquine to corticosteroids
20:22and therefore you increase the efficacy
20:24by about an exposure to by about 20%.
20:27So more daily doses give you more efficacy.
20:31Since the 1970 very high doses of
20:34intravenous methyl prednisolone's
20:36have been used for the treatment
20:38of children with lupus,
20:39they are sometimes referred to
20:42as Poss steroids.
20:43Overall we use them for organ damage
20:46and organ threatening lupus involvement,
20:48but overall the evidence.
20:50What is the right dose of steroids
20:52for children with lupus?
20:54As for adults, with lupus is very Spears.
20:59We recently completed a project to
21:02define what would be the best steroid dose,
21:05but me explaining that to you
21:07will probably take 45 minutes,
21:09so that's way beyond the scope
21:11of this presentation.
21:12Going back to the quality indicator,
21:15these level D evidence and consensus
21:17that calcium and vitamin D sublimation
21:19supplementations should be given
21:21to every child with lupus if they
21:24are treated with steroids for three
21:26or more months.
21:27That's basically almost every child so.
21:29In our center we start treating us
21:33starting calcium and vitamin D very early.
21:36When they start steroids,
21:38we also monitor bone health and
21:40we would start a steroid sparing
21:43medication meaning and immunosuppresants.
21:46If we cannot decrease steroids,
21:48an acceptable dose within three
21:50months and what's an acceptable dose,
21:53it's less or equal 2.15 milligrams
21:56per kilograms per day.
21:59So for all of these items,
22:01these are quality indicators
22:03and consensus was achieved.
22:06Now we talked about intravenous
22:08and oral corticosteroids.
22:09Before I go into the difference how
22:12the bird may work differently in lupus,
22:15I would like to point your attention
22:17to the left side of the slides.
22:20Over here is a Seminole study
22:22from Doctor Pascual's Group.
22:23She is now in New York and
22:27what she did is she did.
22:29RNA expression profiling using
22:31her system that results in these
22:34stories instead of the heat Maps you
22:37may have seen and access patients
22:39with lupus who were not treated
22:42with corticosteroids or who were
22:44on varying doses of steroids,
22:46and then they were or were not
22:49treated with hydroxychloroquine,
22:50and they had various level of
22:53disease activity as measured by
22:55the slide I what she found is that
22:58basically all children with lupus.
23:01Having increased in expression
23:02of type One interference,
23:04that's why all of that is your red.
23:08They are overexpressed.
23:09And then she looked well.
23:11What do oral and Ivy steroids do and
23:14what she found is that irrespective of
23:17whether patients do not get steroids
23:20or are on low dose or high dose steroids,
23:24they have an overexpression
23:25of this type one interferon.
23:27The only way you can get rid of
23:31this interferon one signature.
23:33Is to give a patient Ivy steroids.
23:36If you give up those of pulse steroids
23:39you will suppress the interferon
23:41signature for about a week to 10 days.
23:44Well.
23:45We wanted to see,
23:47well, doesn't matter.
23:49One evidence that it does made on May
23:53matter comes from one of the imaging
23:56studies we did several years ago.
23:59We assessed patients with neuro
24:02psychiatric lupus and the relationship
24:05of their grey and white matter with the
24:09treatment they received and on this.
24:12Picture on the left in yellow
24:16are the areas of.
24:18Preserved white matter that are present
24:21in patients with who were treated with
24:25Ivy steroids rather than oral steroids,
24:28and these areas were basically lost.
24:31So you had a lesser degree of high
24:35quality white matter in children with
24:38lupus who just received oral steroids.
24:41So Ivy steroids in this small study was
24:45able to preserve white matter integrity.
24:50Talking about neuro psychiatric lupus,
24:52well,
24:53you can probably get you know
24:55almost every neurologic and
24:57psychiatric disease with lupus.
24:59And if you look at the classification
25:02for neuro psychiatric lupus,
25:04it almost leads reads like the index of
25:07of a neurology and psychiatry textbooks.
25:10In essence,
25:11numerous psychiatric manifestations
25:13with lupus can be primary or
25:15secondary to the treatment we render.
25:18They can be neurologic or psychiatric's.
25:22Most commonly are cognitive dysfunction,
25:24mood disorders and psychosis,
25:26and among the neurologic
25:28manifestations of seizure disorders.
25:30They also peripheral nervous
25:32system involvement,
25:33but they are rare in children with lupus.
25:38How does one get neuro
25:40psychiatric group as well?
25:41If I knew for sure then I would
25:44get a free flight to Stoke on.
25:47Do the Nobel committee.
25:48But I do not.
25:50The current theory is that there
25:52are certain genetic factors that
25:54predispose patients to get neuro
25:57psychiatric involvements like notation
25:59in IRF 5 interacts one instead 4.
26:01And that there is also it depends on
26:04the regulation of the neuroendocrine
26:06factors and environmental factors.
26:09When these play together,
26:11you will get inflammatory mechanisms
26:13that promote brain involvement or
26:16vascular mechanisms with lupus.
26:18The vascular ones are driven by the
26:20presence with anti phospholipid antibodies.
26:23Order deposition of immune complexes,
26:26what they what happens is then that
26:29there's immune vascular activation.
26:31There is microvascular opathy
26:33cerebral ischaemia and atrophy,
26:35and the neurodegeneration
26:36on the inflammatory side.
26:38We again we see the recruitment of
26:41immune cells that is complemented
26:44micro clear activation.
26:45This leads to direct CNS injury
26:49and neuronal death.
26:50And together these can lead to
26:53the various neuro psychiatric
26:54manifestations of lupus early on.
26:56This,
26:57the manifestations we observe clinically,
26:59I mostly due to functional
27:01changes in the brain.
27:03Your hands are reversible,
27:04but overtime they are mostly
27:06of due to structural damage,
27:08and at that point of time cannot be
27:11treated with anti inflammatories anymore.
27:17When you encounter a child with lupus
27:19with neuro psychiatric manifestations,
27:21the initial diagnostic work up should be
27:24similar to a patient who does not have lupus.
27:28You look for metabolic changes, drugs,
27:30exposures, and then you also want to,
27:33as you know you wanted to do,
27:36and lumbar puncture to exclude infection.
27:40If there are seizures,
27:42you would do an EG.
27:44If their muscle abnormalities,
27:46you would do an EMG.
27:48Almost two in a row imaging and
27:51then there are also certain
27:53autoantibodies that are present
27:55in children with lupus like anti
27:58neuronal antibody and MDR antibodies,
28:00and so on that can that have been
28:03associated with neuropsychiatric lupus
28:04and therefore cannot help you with making
28:08a diagnosis of neuro psychiatric lupus.
28:11If the manifestations are less acute,
28:13you want to do neuro psychological testing
28:16to test for cognitive abnormalities.
28:19Whatever you do,
28:20especially with focal abnormalities,
28:22do a very careful physical examination.
28:26In terms of imaging,
28:28the recommended imaging modality
28:30for a child with lupus is an MRI
28:34of the brain and the spine.
28:36Cities are not that helpful in children
28:40with lupus unless you suspect a stroke,
28:43but what you will see in children with
28:46lupus very typically are this hyperintense
28:49lesions in the paraventricular area,
28:52and you can also see like inflammation around
28:55the spinal canal and cause with lupus.
28:58You mostly have medium and large
29:01vessel involvement of the brain
29:04and MRA and MRV are sufficient.
29:06To depict like shown over here
29:09the sinus vein thrombosis.
29:14What are the treatment for
29:16neuro psychiatric loop as well?
29:18Again, there is little high quality evidence.
29:21Giving Hydroxychloroquine to prevent
29:23brain involvement is a good thing.
29:26Good sleep and helping the symptoms helps
29:29other treatment besides symptomatic.
29:32For, you know if a patient has
29:34depression to give antidepressants and
29:37psychotic sends on cyclophosphamide,
29:39steroids and rituximab are the backbone
29:42of therapy for desperate cases.
29:45Plasma cell inhibitors can be used.
29:48Steroids is a must for March manifestation.
29:51Lower doses are given and for moderate
29:55to severe manifestation higher.
29:57Whatever you do, you will.
29:59Also use especially for severe cases.
30:02Medications like cyclophosphamide
30:03in rituximab.
30:04Cyclophosphamide has been used a
30:07traditionally and there is a current
30:10review showing that you know based
30:12on very few patients that the
30:15relative risk or the benefits or two.
30:18So that means the number needed to
30:22treat for cyclophosphamide is 3.
30:24In other words,
30:25for every three patients with neuro
30:28psychiatric lupus whom you give.
30:30Steroids plus cyclophosphamide he
30:32will have one better outcome compared
30:35to a child who only get steroids
30:38for neuro psychiatric groupers.
30:40Acute improvement with no blur
30:42psychiatric group is always
30:44comes from steroids and not from
30:46cyclophosphamide in a reason here.
30:49Because of the path of the proposed pathway.
30:52Etiology of of neuro psychiatric lupus,
30:55rituximab has become a staple
30:57of NPS early treatment.
31:00And the evidence comes praise
31:02are mostly from a clinical trial
31:05from Daily Doll he used here,
31:07studied a whole potpourri of children
31:10with neuro psychiatric involvement.
31:11Among them were 18 children with MPs,
31:14Ellie.
31:15They were partially with earlier recent
31:18onset of CNS sometimes and some with
31:21longer term and what he found is that
31:24after we took him up plus steroids,
31:2785% of the children had a
31:30good response by six months.
31:33If you look on the figure on the right,
31:36the blue shading represents the
31:38neuro psychiatric impairment.
31:40And with treatment of.
31:44This treatment with rituximab,
31:45as you can see,
31:47the blue shading goes down so the
31:49patient improved and that was true for
31:51patients with recent onset but also
31:53with longer standing and PSLE sometimes.
31:56So that also means for you if a
31:58patient who seems to be not doing
32:01well in terms of brain disease
32:03trying rituximab could be a good
32:05option for this patient.
32:07The problem with this treatment
32:09is relapse after year or year and
32:11a half there for maintenance.
32:13Therapy is very often needing.
32:15And most commonly mycophenolate
32:16Moffitt L is used.
32:21Moving on to the kidney.
32:25Manifestation of lupus for flu plus
32:28nephritis. Include him, aturia,
32:30proteinuria, and edema as well
32:32as blood pressure abnormalities,
32:35both 'cause they're all very nonspecific.
32:38A kidney biopsy is recommended or ask
32:42for to diagnose a persons with lupus.
32:46It is recommended that every
32:48child with lupus should get.
32:50A kidney biopsy,
32:51if they have new onset of proteinuria or
32:55a clinical relevant worsening of renal
32:57function or an active renal sediment.
33:00A person with lupus nephritis should also
33:02be seen in clinic every three months,
33:05and this is because lupus nephritis
33:07can change quite quickly and you would
33:10not want to have a patient having
33:12active kidney disease for a long time
33:14because we do know that uncontrolled
33:16kidney disease has a market detrimental
33:19effect on long term survival of the children.
33:22Unfortunately,
33:22with doing a kidney biopsy,
33:24when a patient has more than or at
33:27least 500 milligrams of protein in the
33:30urine makes us diagnose most patients
33:32with lupus when they also already
33:35have class 3 for lupus nephritis.
33:37That means they already have
33:39advanced manifestations of the
33:41renal involvement and always will
33:43need immunosuppressive therapy,
33:44and it needs to be started quickly to
33:47avoid damage for children with lupus
33:50who have ongoing proteinuria ASEN.
33:52OP inhibitors and are warranted,
33:54especially if they have proteinuria
33:57of 400 milligrams or more,
33:59and this is because it has been shown
34:02that ongoing proteinuria is a further
34:05risk factor for chronic kidney disease.
34:12How do we measure proteinuria
34:14in children with lupus?
34:16Do not do a urine dipstick.
34:19Turns out a dipstick measure
34:21correlates with lab, urine,
34:23protein, creatinine ratio,
34:24or 24 hour urine measurement
34:26of proteinuria by about .2.
34:28So it's going to be very inaccurate and
34:32save yourself the money for the urine step.
34:35What you can do is you can do a random
34:39protein creatinine ratio from a.
34:42Random urine sample or an album
34:44in creating ratio and whether
34:46you do the one or the other,
34:48it doesn't matter.
34:49It basically gets you the same
34:51results as has been shown here in
34:54a very sophisticated analysis.
34:55What is important to know is that you
34:58can only use a random urine sample if
35:01the protein creatinine ratio is 1.0 or less.
35:04And why is that?
35:05Because if you have higher
35:07protein to creatinine ratio.
35:09The measure in the urine you get from
35:12the random spot sample will only
35:14correlate .3 with the true proteinuria
35:17as measured by a 24 hour urine.
35:19So it's mildly correlated with the results,
35:22and if you want to know really
35:24how much protein is in the urine,
35:27you will have to do a 24 hour urine.
35:30There is some additional rationale
35:32behind it because different
35:33from other plumber alone,
35:35diseases with new personnel frites,
35:37you have a dye or a variation of proteinuria.
35:40So if there is a lot of protein
35:42you will not have a good result
35:45just by virtue of measuring protein
35:47or albumin in the urine.
35:50Random urine sample.
35:55Because most children with lupus will
35:57be diagnosed with lupus nephritis
35:59that all of class three and four.
36:02That means when it's already advanced
36:04that need induction therapy and
36:06followed by maintenance therapy,
36:07like in a cancer patient,
36:09typically or traditionally,
36:10induction therapy is 6 months and
36:13maintenance therapies anywhere
36:14from three to five years.
36:15Those levels see evidence and consensus.
36:18The children with lupus nephritis
36:19should either be treated with
36:21Mycophenolate Moffitt here.
36:23Or cyclophosphamide and the doses of
36:25mycophenolate are written down here,
36:27for which it will be achieved consensus.
36:32For cyclophosphamide,
36:33typically the NIH regimen that
36:35was defined in the 1917 is used.
36:38So we start with 500 milligrams per
36:40meter square, and then goes up until
36:43we get about 1500 milligrams per month.
36:46And but we watched the nature of the WBC
36:50count 7 to 10 days after the infusion,
36:53and this is done to make sure that one
36:56doesn't get too much in Eunice suppression,
36:59it has been joining independent studies.
37:02But if the natives under 3,
37:04the risk of yatra genic
37:07infection is markedly higher,
37:09so you want to observe that that values
37:12is there irrespective of whether you
37:15mus mycophenolate or cyclophosphamide.
37:18The current therapies are only about 56
37:21or 60% effective in achieving remission.
37:25In the case of of Mycophenolate Moffitt here,
37:29it's 56%.
37:30It's the same for cyclophosphamide.
37:32What has been shown in some studies that
37:36mycophenolate dosing should be personalized?
37:39And that can be done by
37:41appreviated PK profiling,
37:43which can be done at your farmer
37:45clinical pharmacology Department.
37:47And if your personalized mycophenolate
37:49dosing to your patient then you
37:52actually your success rate for getting
37:54a chart in renal remission by the end
37:57of induction therapy is almost 90%.
38:00If you do it,
38:02the usual an convenient way and
38:04just dose by body surface area,
38:06it will only be 56%,
38:08so that's the slacker factor,
38:10the target exposure to mycophenolate
38:12is anywhere between 60 and 90
38:14milligram per hour per liter.
38:19What about cyclophosphamide the
38:21effectiveness and overall safety are
38:23similar to that of mycophenolate.
38:25However, the big difference is
38:27ovarian damage and ovarian failure.
38:29When you look in the literature,
38:31the mean risk for variant failure in
38:33a child with lupus and a girl with
38:37lupus after completing cyclophosphamide
38:39therapy for lupus is 11%.
38:41We did a study a couple of years back
38:44and we found that after six months
38:47of induction therapy for lupus,
38:49nephritis, or CNS lupus.
38:5130% of the females will have.
38:54A decreased ovarian reserve,
38:56and that means that 30% will have
39:00increased problems with becoming pregnant.
39:03The risk of ovarian damage is not as
39:06that are shown in the literature or the
39:09cumulative dose of cyclophosphamide,
39:11but there is more to it as you
39:13made it use purchased.
39:15Looking at this wide range of
39:17dosing that has been proposed as a
39:20threshold of causing ovarian damage,
39:22it depends on the time as compared
39:25to menstrual cycle.
39:26Cyclophosphamide is infusing.
39:27It also depends on some genetic
39:29factors increase.
39:30Indeed,
39:30persons who have this Geno type
39:33will have a 5.
39:34Fold higher risk of having ovarian
39:37damage with cyclophosphamide compared to
39:40females who do not have that genotype.
39:42It's too far for me to go into
39:45the different ways to protect,
39:47to provide ovarian protection.
39:49It can be achieved by high doses of
39:52generator ironists in the referral to
39:54a prior clinical trial I completed.
39:57In 2015 so going back to induction
40:02therapy so we have seen we have said
40:05that in order to diagnose lupus
40:07nephritis you need a kidney biopsy.
40:09Now there was no consensus achieved as
40:12part of the quality indicators where
40:15the kualoa up biopsy should be done.
40:18Why would you do a follow-up biopsy
40:20after you completed induction therapy?
40:22Well,
40:23the reason is shown on the
40:25right side of this slide.
40:27If, after induction therapy,
40:28your patient has normal cheer for.
40:31And basically no proteinuria
40:33if you look histologically,
40:34that patient will still have a 30%
40:37chance of having active lupus nephritis,
40:40meaning an inflammatory process that will
40:43undoubtedly harm the kidney overtime.
40:46On the other hand,
40:47if you have a patient with an
40:49abnormal cheer for and with
40:51still some sizable proteinuria,
40:52they will have only a 60% chance effective
40:55of having active lupus nephritis.
40:57And the reason is that proteinuria
40:58can also be a sign of kidney damage,
41:01and by virtue of looking in the urine,
41:04you would not know.
41:07Has been shown very elegantly while
41:09I'll go darred are in a paper from
41:12coming from Argentina and she looked
41:14at patients with lupus nephritis after
41:17six months of induction therapy.
41:19They were complete responders,
41:21denoted as CR and partial responders
41:24and then the Dietrich follow-up
41:26biopsies and in the.
41:28And based on what they found in the kidney,
41:31they could not say how much.
41:35Chronicity was there and it could
41:37also not deduce for those who
41:39had chronicity from Lupus,
41:40who was really a partial,
41:42and who was a complete responders.
41:44So the dot is, your apps are really
41:47overlapping, and it means again,
41:49but I showed you on the right side that
41:52you almost need histologic confirmation.
41:54Be 'cause your clinical
41:57assessments are not reliable.
41:59The value of repeat kidney biopsies
42:01at six months to one year to verify
42:04response to induction therapy and at
42:07about two years to verify efficacy of
42:10maintenance therapy have been proposed,
42:12but they are currently not
42:14standard of clinical care.
42:16It has been shown, however,
42:18if a patient on repeat biopsy at
42:21about six months to 12 months after
42:24they started induction therapy.
42:26If there is no active lupus nephritis
42:29as measured by the NIH activity index.
42:32Then the chances of we know
42:35survival at 10 years is 100%.
42:39However, if their activity index is 122,
42:42the highest is 24 then there.
42:46Chances of renal survival go down to 80%
42:49and if it's higher than two it's 44%.
42:52So knowing what's going on after
42:54you seem to have completed induction
42:57therapy is important because arguably,
42:59if you still saw a lot of inflammation,
43:03you would personalize the care of
43:05this patient and give more immune
43:07suppression rather than cutting
43:09back on immunosuppression.
43:10What you normally do for maintenance therapy,
43:13as you only try to preserve.
43:16Disease Control rather than
43:20eliminating inflammation.
43:22S with arm.
43:25Histologic activity on kidney biopsy.
43:27The decree of kidney damage on repeat
43:30biopsy will help you to educate your patient.
43:33If on follow up kidney biopsy at
43:376 to 12 months.
43:39The patient has a chronic
43:41chronicity score of four or less.
43:43The range goes from zero to 12.
43:45Then they have a very good chance
43:48of renal survival into 10 years.
43:50However, if it's more than
43:52four for every point over four,
43:54there is a 30% increase.
43:5730% risk of an increase in the
44:00serum creatinine over the next 10
44:02years and that means they will
44:04go into chronic kidney disease.
44:12Another quality indicator for children
44:14with lupus is that you should strive
44:17to Co manage in your patients with
44:20lupus with you under ologist and why
44:23is that we cause hypertension is
44:25very common in children with lupus.
44:27It's can be easily explainable due to
44:30the fact that Lupus is a vasculopathy.
44:34We recently did a study where we looked
44:36at our cohort in Cincinnati and we
44:39found that out diagnosis and we hadn't
44:41started steroids at that point of time.
44:4429% of the children with group
44:47is already had hypertension.
44:49And some of them had renal disease,
44:51but many of them did not.
44:54And then we followed them for
44:56almost 3 or 2 1/2 years.
44:58And what we saw as much to the
45:01dismay of our quality director is
45:03that our hypertension control didn't
45:06get better on a cohort level or not
45:09markedly and still one out of five
45:12children with lupus had hypertension.
45:15Risk factors for hypertension was obesity,
45:17lupus, nephritis,
45:18and high extrarenal disease activity
45:20and at the follow up again it
45:23was lupus nephritis and obesity.
45:25What is recommended and what we do
45:27very often in Cincinnati is we do
45:30ambulatory blood pressure monitoring.
45:32That means a patient with lupus.
45:34It's very popular,
45:35can guarantee you they get their blood
45:38pressure measured every 20 to 30
45:41minutes during the day and at night.
45:43The machine also measures the heart rate.
45:46And it's there. It makes multiple readings.
45:50Obviously during a 24 hour period.
45:54One of the outputs is the blood
45:57pressure load,
45:58meaning the percentage of measurements
46:00exceeding the negative with percentile.
46:02For patients age and height.
46:04And also the tipping status,
46:06meaning the percentage decrease
46:08of blood pressure during sleep.
46:10As you know your blood pressure
46:13during sleep goes down by 15 to 20%.
46:16So what did they find in children with lupus?
46:19It's exemplified here, right into studies.
46:22A pilot study of 52 children
46:24coming from Texas children.
46:25All of them had normal kidney function,
46:28all of them.
46:29None of them had active lupus nephritis.
46:31And what they found is that
46:34there was nocturnal hypertension
46:35in almost half of them,
46:37and there was an abnormal tipping
46:39set in the vast majority of them,
46:41it was repeated in another study that
46:44was done earlier, but principle boy.
46:46With similar results.
46:48Lot of nocturnal hypertension
46:49and a lot of optoma dig status.
46:53Well, why should you care?
46:55Well,
46:55because we do know that abnormal
46:58ambulatory blood pressure
47:00measurements are associated with
47:02left ventricular hypertrophy in the
47:04general population and by extension
47:07of that also in children with lupus.
47:09We know that mask hypertension in
47:12children can is an independent risk
47:15factor for chronic kidney disease.
47:17And abnormal blood pressure
47:19measurements are also associated with
47:22incident or increase in proteinuria.
47:26Talking about the quality indicator,
47:28there was consensus that we should
47:31educate as pediatric rheumatologist
47:33and nephrologist about cardiovascular
47:34X Factor because you may know that
47:37the that if you have a person,
47:39a woman between the ages of 30 and 40 in the
47:44emergency room and she has a heart attack,
47:47the most likely diagnosis is lupus,
47:50so the cardiovascular risk of
47:52adults with lupus is sizable.
47:54It's important that we educate.
47:56Our patients and their parents
47:57so that they don't smoke or don't
48:00smoke around the patient that we
48:02wanted a blood pressure we monitor.
48:04Wait, we monitor for diabetic risk
48:07factors and also lipid levels and that
48:10should be done with the patient and the
48:13family at least every one to two years.
48:16There was also consensus among these
48:19experts that vaccination should be
48:21given to all children with lupus.
48:23The annual influenza vaccine,
48:24as you would do with every
48:26pediatric patients,
48:27but also vaccination for all except
48:29encapsulated Organism including pluma caucus,
48:31Haemophilus sentiment caucus
48:33and also for the HPV vaccine.
48:35And even if a patient is on
48:37high doses of steroids,
48:39you will still have a good chance
48:42of seroconversion and that's one
48:44of the cancers in female you
48:46can avoid by giving the vaccine.
48:49When you vaccinate children with lupus,
48:51you need to observe the vaccination
48:53schedule for immuno compromised children.
48:55What do we know about the efficacy of
48:58vaccinations in persons with lupus?
49:00We know that the flu shot does not
49:03increase the risk of lupus flare and
49:06may hypothesize that the activation
49:08of the immune system after the
49:11shot could cause a flare.
49:12It does not, however,
49:14the production of anti for
49:16celebrities transient Lee increased.
49:17You want you should be measuring
49:20postvaccination titers in patients
49:22on high dose steroids,
49:23meaning to.
49:24Milligrams per kilograms or more than
49:2620 milligrams per day or after the
49:29rituximab be 'cause the vaccination
49:31response rates are planted and you
49:33will also have a decrease in Murph.
49:35You also will have a decrease in
49:38the hepatitis B vaccine if you
49:40give your patient and then.
49:47In terms of transfer of care, yes,
49:49you should transfer your patient.
49:50When is the best time?
49:54It's difficult to say.
49:55It really depends on your local setting,
49:58on the resources a patient has and the
50:01resources the adult asserting has.
50:04What I do really like is this template
50:06from the American College of Rheumatology,
50:09which summarizes the course of
50:11a patient with lupus easily and
50:14quickly so that the pediatric
50:16rheumatologist is not overburdened
50:17and that the adult rheumatologist
50:19who receives the patient can see the
50:22most pertinent information quickly.
50:27That gets me to the end of my presentation,
50:29where I would like to give
50:31you some take home messages.
50:32I hope I conveyed to you that the care
50:35of children with Lupus takes planning
50:37and monitoring for good outcomes.
50:39Plan your clinic visit.
50:40You plan the standardized evaluation
50:42and you monitor the outcomes.
50:43If you don't know where you are,
50:46you can't have a good way forward
50:47and develop a therapeutic.
50:49When the quality and the haters
50:51are available to you to help you
50:54set up your clinic accordingly.
50:56Hydroxychloroquine is for
50:57all children with lupus.
50:58I advertise it to my patients
51:01as a lupus vitamin.
51:02But you need to check the dose carefully
51:06and you need to check the eyes.
51:08Vaccinations are important
51:09for children with lupus.
51:11Given their increase risk of
51:13infections and also cancers.
51:14But he used the schedule for
51:17immunosuppressed children.
51:18Wanted for neuro psychiatric lupus.
51:20One of the tools we use in clinic
51:23is a software called the P 9:00 AM.
51:26We do baseline MRI's of the
51:28brain in the spine.
51:29So if you were to have a patient who
51:32develops neuro psychiatric abnormalities,
51:34you have a baseline image to
51:36compare the finding imaging
51:38findings to for lupus nephritis.
51:40Can use mycophenolate but I would
51:42advise you to check your medication
51:44levels and there is a very and
51:47protection for girls who are
51:49tennis stage two or higher cycle.
51:51There is no protection from Ganado
51:54toxicity of cyclophosphamide
51:55for males with lupus.
51:59At this time I would like
52:01to thank you for attention.
52:03Show your Cincinnati here is just
52:06under under Chicago, 600 miles South.
52:08The famous River boards that's Doctor Salk.
52:11Sabin with his vaccine and these
52:13are some of the achievements
52:15of Cincinnati Children's which
52:17I will not going to because I
52:21know it's time for questions.
52:23Thank you for attention.
52:33Thank you so much, so let your brother
52:37I'll just I'll start while Paul
52:39Unmutes himself. So first question
52:42is you know I'm a pulmonologist.
52:44I would particularly a tree or
52:47pulmonologist and Sleep Medicine and
52:49was intrigued by your discussion
52:51about the nocturnal hypertension.
52:53And so I wonder if there are
52:57guidelines about screening for sleep
52:59disorders such as obstructive apnea
53:01or periodic limb movement disorder.
53:03In which there is a higher prevalence
53:06in kidney disease given those findings,
53:09and especially in Association with obesity.
53:13I just want to say make.
53:15My sense is that it's associated
53:17with obesity and a child
53:19with lupus who is obese would
53:21need those studies for sure.
53:23There's also pulmonary
53:24involvement with lupus, but.
53:26You know it's it's less
53:28so in a chronic fashion,
53:29and it's less common in children as
53:31compared to adults where you can
53:33see some interstitial lung disease.
53:36Great thank you, Polly. See you're unmuted.
53:40Yes, can you hear me yes perfectly.
53:45I meant, done.
53:47The Covid vaccine and the use of
53:50Rituxan Mab I I have anecdotal seen
53:54anecdotal reports about concern of.
53:57Lack of a B cell response too.
54:00To the covid vaccine. After
54:04obviously nobody has the complete answer,
54:06would like to refer you to the website
54:09of the American College of Rheumatology.
54:12They have developed very nice guidance
54:15for the use of for the timing of
54:18covid vaccination in relation to
54:20intake of immunosuppressive therapy,
54:22whether they should be continued,
54:25whether should be held for a week
54:29or longer around the time of.
54:32Covid Vaccine Vaccine Administration
54:33for rituximab.
54:34The further away from the infusion,
54:37the injection is the bed it is.
54:40Remember it took some app is
54:42only given like once a year.
54:45We recently had a patient from needed.
54:48Rick talks him up for a brain
54:51disease and beside decided to
54:53immunize the patient first against
54:55Covid because the acute response of
54:58CNS lupus comes from the steroids
55:00and not from the rituximab.
55:07Other questions.
55:10So Paul, it looks like there
55:12are some questions in the Q&A.
55:14I'll just ask.
55:15The first one is Doctor Berner.
55:17Do you have any recommendations
55:19for specific support groups
55:20for teens dealing with lupus?
55:24We have tried years ago face to face
55:27meetings with with adolescents with lupus.
55:30They did not go down well.
55:32We found more acceptance with web
55:34based meetings and the Lupus Foundation
55:36of America has like a very active
55:39chat room for both girls and males
55:42with lupus and sometimes boys with
55:44lupus feel feel left out because
55:46when they look on the website they
55:49see nothing but women who have the
55:52disease and then they have it too. So.
55:58Having support for pain and and
56:01the burden of the disease and
56:03the stigma associated with it,
56:05you know on a web based fashion, is useful.
56:09Having patients meet face to face
56:12was less easy to be done and I
56:14think one of the reasons is cause
56:17children always need to be driven
56:20to every event and another lesson
56:22don't necessarily want to have
56:24their parents sitting next to them.
56:27When they talk about their feelings.
56:31Doctor Bernard,
56:32there's a question from Kathleen
56:34Corbin from pediatric rheumatology.
56:36Do you check a spine MRI and
56:38all patients being evaluated for
56:40neuro psychiatric lupus?
56:42We usually do brain unless
56:44there are specific symptoms
56:45suggestive of spine involvement.
56:48We look in both areas and the reason
56:51is we want to get a baseline evaluation
56:55and we would not want to miss some mild.
56:58If you have a patient who has
57:01overed neuro psychiatric symptoms,
57:03you may miss these final abnormalities,
57:05but you know it may have a long term
57:08consequences on patient outcome.
57:10If I know that there is transverse
57:13myelitis or changes in the spine,
57:15the treatment will be quite aggressive.
57:18So we do both.
57:20Doctor Corbin also asked that.
57:24Repeat kidney biopsy for all
57:26lupus patients at one year.
57:28Yes, that's fine.
57:29Anywhere between six months in a year.
57:31Would we have done as we introduced
57:34the repeat biopsy concept at
57:36the time of diagnosis and we
57:38have we engage our neurologists.
57:42If so, if a patient is aware at baseline
57:45that a follow up by absolutely come,
57:48then it doesn't come out of the blue.
57:51If you ask them for the repeat biopsy.
57:54Conversely, if you never
57:56confessed to the kidney biopsy,
57:57the follow up kidney biopsy,
57:59it's a harder concept to implement.
58:04Question from Karen Riley.
58:06Do you have any recommendations for
58:09specific support groups for teens,
58:11teenagers dealing with lupus?
58:16What we have done, and I don't know
58:19whether that captures what you kind
58:21of alluding to because I tried in
58:24court to answer that question already,
58:26we developed that each program
58:29which has been published.
58:31In pediatric rheumatology online,
58:32which give provides a special
58:35outline for cognitive behavioral
58:37therapy for children with lupus.
58:39So if you have a psychology program
58:42they could use that CBT approach
58:45to help children with lupus.
58:53Question about. Do you have any
58:56experience or any thoughts about?
58:58Treatment with rituximab followed by
59:02Benlysta since they affect the cells.
59:06By different mechanisms.
59:09There is a clinical trial ongoing
59:11that addresses that issue.
59:15It has been used.
59:16It was a clinical trial of rituximab in
59:18lupus nephritis, and it was negative.
59:21It was negative for the primary,
59:23secondary, and exploratory outcomes.
59:25It was negative.
59:26So we do know that after.
59:30That you can have an increase in
59:32in bliss levels of with rituximab.
59:35So it makes sense to combine both.
59:37But the clinical trial
59:39has not been published.
59:40In my experience,
59:42giving a lot of rituximab to
59:44children with lupus can get you into
59:46very into high program situation
59:48where you then have to supplement,
59:51sometimes for several years.
59:53A patient with Ivy IG.
59:58Well. Paul, can I
01:00:01just ask one more question before
01:00:03we close is is Doctor Brenner?
01:00:05Can you just expand on the risk of
01:00:08cancers which you kind of alluded to from?
01:00:11You know? I guess I assume
01:00:13adults with child onset lupus?
01:00:15What sort of types?
01:00:16And at what age you know,
01:00:18was the presentation?
01:00:21Most of them were lymphoma and there
01:00:23were anywhere between three and
01:00:25five years after diagnosis with the
01:00:27disease that data came was published
01:00:29in Lupus a couple of years back,
01:00:31and it came from a population based
01:00:34study that was done by Doctor Ann Clock
01:00:36and we were participants in children
01:00:38compared to adults where the three and
01:00:41a half times higher risk of cancers.
01:00:45Great, thank you Paula. Let you close.
01:00:50Doctor Bernard we greatly appreciate
01:00:52the fine chalk you gave today
01:00:55and also joining us for the
01:00:57annual Mary Jane Keller Lecture.
01:00:59I think all of us have been
01:01:01highly informed by your discussion
01:01:03of these aspects of lupus,
01:01:06so thank you very much. Well,
01:01:09thank you for having me have a wonderful day.
01:01:11Yeah, thank you so much.
01:01:13Play.